Use of stearate in an inhalable formulation

ABSTRACT

The present invention concerns a method for making an inhaled pharmaceutical composition with improved powder handling properties comprising a stearate, a method of preparing such a composition, and the use of such a stearate in a composition when dispensed into a receptacle for use in a dry powder inhaler receptacle.

RELATED APPLICATIONS

This application is a Continuation of U.S. Ser. No. 14/779,382, filed onSep. 23, 2015 which is a United States national stage of InternationalApplication No. PCT/GB2014/051003, filed Mar. 28, 2014, which waspublished as International Publication No. WO 2014/155134 A1, and whichclaims benefit of United Kingdom Application No. 1305825.0 filed, Mar.28, 2013, the entire contents of which are hereby expressly incorporatedherein by reference thereto.

A process is disclosed for preparing a formulation to be administered asdry powder for inhalation suitable for effective delivery of an activeingredient into the lower respiratory tract of a patient. In particular,a process is disclosed for preparing a pharmaceutical compositionsuitable for inhalation, the formulation having improved filling andhandling properties.

BACKGROUND AND PRIOR ART

The efficient dispersal of an active pharmaceutical ingredient is ofutmost importance in the field of respiratory medicine. In this field,it is generally desirable to employ therapeutic particles with a size(i.e. geometric diameter) in the range of 1 to 10 μm or an aerodynamicdiameter of 1-5 μm in order to be delivered to the lower respiratorytract. Particles above these sizes tend to impact in the regions of theupper airways and are removed by the mucocilliary escalator.

Pulmonary drug delivery, therefore, must overcome the technicalchallenges of working with fine particles but still operate within theconstraints dictated by human anatomy.

To facilitate delivery of cohesive powders a number of solutions havebeen provided in the art.

Inhaler Devices

Firstly, inhalation devices have been developed for assisting with thedelivery of cohesive micronised medicament to the lungs of patients.When a patient actuates a DPI device it produce an air stream, the flowof air produced by the patient's inspiratory manoeuvre lifts the powderout of the inhaler (“Fluidisation”) and causes the separation of, interalia, the drug from carrier (“De-agglomeration”).

Dry powder inhalers can be divided into two basic types:

-   i) single dose inhalers, for the administration of pre-subdivided    single doses of the active compound from a pre-metered dosage means    such as a capsule or single blister tab;-   ii) multidose dry powder inhalers (MDPIs), either with    pre-subdivided single doses or pre-loaded with quantities of active    ingredient where the drug is stored in a reservoir or blister    pack/strip); each dose is created by a metering unit either within    the inhaler or within the filling line prior to assembly.

On the basis of the required inspiratory flow rates (l/min) which inturn are strictly depending on their design and mechanical features,DPIs are divided in:

-   i) low-resistance devices (>90 l/min);-   ii) medium-resistance devices (about 60 l/min);-   iii) high-resistance devices (about 30 l/min).

The reported flow rates refer to the pressure drop of 4 KPa (Kilopascal)in accordance to the European Pharmacopoeia (EurPh).

For powder inhalers which release the medicament from pre-dosed units,e.g. capsules or blister packs, the same restriction applies for thelow-friction operation of the filling apparatus for these unit doses.This low-friction operation is greatly improved with free flowing powderis used, for example by using large carrier particles.

Large Carrier Particles

Numerous approaches have been adopted to manipulate DPI particulateinteractions. A further approach to improve the efficiency of most DPIformulations employs carrier particles as a means to overcome powderhandling problems. The majority have focused on the physical propertiesof the carrier, specifically modifying the shape, size, or rugosity ofthe carrier. Other approaches have focused on producing uniformrespirable drug particles by spray drying or supercritical fluidprecipitation.

Lactose is the most common carrier used and can constitute more than 99%by weight of a DPI formulation. Lactose carrier particles aretraditionally used as a flow aid and they assist with carrying the doseof the active into the lungs. The chemical and physical properties oflactose play an important role in DPI formulations. The selection of thespecific grade of lactose is based on the inhaler device, the fillingprocess and the required API release profile. Critically, DPIformulations need to be homogeneous however this is not the onlyparameter requiring consideration. The adhesion between carrier and drugparticle should not be too strong because the drug will not be able torelease from the lactose particle during inhalation. Likewise, it shouldnot be so weak that the carrier separates from the carrier duringroutine powder handling. Furthermore, the drug should always be releasedfrom the carrier in the same way. One of the important parameters forthe formulation is the particle size of the lactose.

Carrier particles or excipients, such as lactose, for inhaledtherapeutic preparations also include significantly larger diameterparticles (e.g. 50 to 300 μm) that typically do not penetrate into therespiratory tract to the same degree as the active ingredient.

The most common approach for describing formulations with multiplecomponents (i.e. drug and carrier) is to use laser diffraction analysis.Machines such as the Malvern Mastersizser report results as sectionsnamely the D₁₀, D₅₀, and D₉₀ values based on a volume distribution. TheD₅₀, the median, is defined as the diameter (in microns) where half ofthe particle population, by volume, lies below this value. Similarly,the D₉₀ is the value wherein 90 percent of the particle distribution, byvolume, lies below the stated D₉₀ value, and the D₁₀ is the value belowwhich 10 percent of the particle population resides on a volume basis.

The lactose particle size and distribution will also, in many instances,significantly influence pharmaceutical and biological properties, suchas, for example, bioavailability. For example, it is well known thatcoarse lactose in crystalline form has a good flow rate and goodphysical stability whereas fine lactose powder, such as that produced byconventional fine grinding or milling, generally lacks good flowproperties. Lactose prepared by conventional spray drying either lacksdesired flow properties or contains too many large sized lactosecrystals.

It is well known that one particular drawback associated withconventional means of producing pharmaceutical grade lactose relates toundesirable variations in particle size, morphology and distribution.Such production methods are particularly problematic in that they oftenlead to excessive and undesirable variations in the fine particle mass(“FPM”) of the delivered pharmaceutical active.

Lactose morphology is believed to be another important parameter tocontrol, and it is believed that the degree of surface roughness caninfluence the interaction between the lactose particle and excipient andas such is now often measured as part of the lactose selection criteria.

In general, it is preferable to use smaller particle sizes for thelactose or a blend of coarse and fine particles lactose becausereduction in mean particle size of the lactose has been shown toincrease the aerosolisation of various drugs but this smaller sizeselection is marred with poor flow properties. Therefore until now theroutine approach has been simply to use as few fines particles aspossible.

Small Particles

Fine particles are, by their nature, cohesive, and whilst simplyblending the large carrier particles, additive particles and fineexcipient particles together will result in occupation of thehigh-energy sites on the carrier particles by additive particles, thedistribution of the additive particles over these sites will bedetermined by the amount of energy that is used in the processing step.

One explanation for this observation is that the fine lactose particlesoccupy areas of high energy on the carrier surface, such as the clefts.With these high energy sites occupied by the fine lactose particles, thedrug particles will then preferentially adhere to the lower adhesionsites and consequently the drug will be more easily released. A furtherbenefit of lactose fines is the surface area increases substantially andthe potential payload of each carrier also increases.

Fine particles (“Fines”) are characterized as particles with a D₁₀ below5 μm, D₅₀ below 15 μm and D₉₀ below 32 μm as determined by laserdiffraction particle size analysis, for example a Spraytec withInhalation Cell, Malvern Instruments, Malvern, UK. A balance, however,needs to be struck between desirable API detachment and prematuredetachment due to poor API adherence to the carrier. Whilst the presenceof high lactose fines may increase the aerosol performance of aformulation, this comes at the cost of poor powder handling e.g. inconveying and filing processes.

Fine particles tend to be increasingly thermodynamically unstable astheir surface area to volume ratio increases, which provides anincreasing surface free energy with this decreasing particle size, andconsequently increases the tendency of particles to agglomerate. Theprocess of filling from hoppers, may result in the agglomeration of fineparticles and adherence of such particles to the walls of the hoppers.This is a problem that results in the fine particles leaving the hopperas large, stable agglomerates, or being unable to leave the hopper andremaining adhered to the interior of the hopper, or even clogging orblocking the hopper. Poor flow from powder hoppers can adversely affectmanufacturing operations. The uncertainty on the extent stableagglomerates formation of the particles between each dispension of thefiller, and also between different hoppers and different batches ofparticles, leads to poor dose reproducibility. Furthermore, theformation of agglomerates means that the MMAD of the active particlescan be vastly different with agglomerates of the active particles, onoccasion, not reaching the required part of the lung.

As particles decrease in size, they become lighter resulting in atransition away from gravitational forces towards interparticulateforces becoming the predominate force. Conversely, as particles increasein size, they become heavier resulting in a transition away frominterparticulate towards gravitational forces becoming the predominateforce. Smaller particles, therefore, become overwhelmed by the forces ofcohesion and adhesion which is why they adhere to one another and formagglomerates or aggregates. The likelihood of cohesion increases withdecreasing particle size; particles smaller than 100 nm experience anelement of cohesion. This degree of cohension increases with decreasingsize.

Micronisation of the active drug is essential for deposition into thelower lungs during inhalation. As a general rule, however, the finerparticles become, the stronger the forces of cohesion and/or adhesionbetween these particles. Strong cohesion/adhesion forces hinder thehandling of the powder during the manufacturing process especiallypouring and filling of powders. Moreover micronisation or the presenceof micronized particles reduces the ability of the formulation to pouror flow freely under gravity (“flowability”).

The effect of non-lactose fine excipients on FPD or FPF performance ofternary formulations has also been investigated. Fines of erythritol,glucose, mannitol, polyethylene glycol 6000, sorbitol and trehalose haveall been found to increase either the FPD or FPF of a variety of drugswhen added. Fines of different materials have produced varying increasesin formulation performance compared to each other and to lactose fines,with lactose fines producing poorer, equal and better performance invarious studies.

Lactose Fines

The beneficial aerosol effects of fines on an inhaled formulation havebeen demonstrated through the use of pre-treatment steps in whichpre-existing (intrinsic) fine particles were removed from coarse lactosecarrier by either air-jet sieving or air washing lactose held on asieve. The removal of lactose fines was found to decrease the aerosolperformance of formulations containing a variety of different drugs,which were blended by different techniques and aerosolised fromdifferent inhalers. Such results are in accordance with numerous studieswhich, when using various grades of carrier material, different inhalersand different drug found that those containing the highest proportion ofintrinsic fines gave the greatest aerosol performance (Jones & Prices,2006).

Consequently, the majority of research in this area has focused on theaddition of lactose fines to blends of coarse lactose (typically a 63-90μm size fraction) and drug. The fine lactose typically used had a volumemedian diameter (VMD) of 4-7 μm and the proportion added was typicallyin the range 1.5 to 10%, but proportions as high as 95% have beeninvestigated (Jones & Prices, 2006). Fine lactose in an amount as highas 95% (w/w) leads to highly cohesive formulations.

In addition to pacifying active sites, the addition of fine additiveparticles may also lead to the formation of fine lactose agglomerates.These lactose agglomerate particles can remain adhered to the coarsecarrier lactose during processing and handling and may dramaticallyreduce the inspirational energy requirements in entrainment andde-aggregation of the drug particles following aerosolisation.

Despite the beneficial aerosol performance imparted by lactose fines,the addition of fines to a formulation has been found to increase devicedrug retention, the effect has been attributed to either the decreasedflowability of powders containing a higher proportion of fine particles.The increased adhesiveness of fine particles is thought to reduceflowability of the entire powder blend in formulations containing finescontents above 10% by weight of the entire formulation. Consequently,despite the beneficial aerosol improvement, there has been a reluctanceto use a fines content above 5% by weight of the entire formulationbecause of the poor powder flow properties of such formulations. This isbecause lactose fines can increase the occurrence of powder bridging inan inhaled formulation. Powder bridging is the process whereby particlesin a powder bed get stuck and jam against one another creatingsemi-permanent structures in the powder bed. Significant time andresource is required to identify, locate and disrupt these powderbridges before powder filling can resume. Sometimes these semi-permanentstructures can break apart just prior to filling into a DPI. The powdersurrounding these powder bridges is often not homogeneous resulting inatypical formulation (high or low API content) entering the blisters,capsules, reservoirs of the filling line.

WO 2011 067212 discloses a fine lactose fraction. The ‘fine’ lactosefraction is defined as the fraction of lactose having a particle size ofless than 7 μm, such as less than 6 μm, for example less than 5 μm. Theparticle size of the ‘fine’ lactose fraction may be less than 4.5 μm.The fine lactose fraction, if present, may comprise 2 to 10% by weightof the total lactose component, such as 3 to 6% by weight fine lactose,for example 4.5% by weight fine lactose.

WO 1995 011666 describes a process for modifying the surface propertiesof the carrier particles by dislodging any asperities in the form ofsmall grains without substantially changing the size of the particles.Said preliminary handling of the carrier causes the micronised drugparticles to be subjected to weaker interparticle adhesion forces.

EP 0 663 815 describes the addition of finer particles (<10 μm) tocoarser carrier particles (>20 vim) for controlling and optimising theamount of delivered drug during the aerosolisation phase.

Lactose fines are not the only component available for manipulating thehigh energy sites on carrier particles and they may be used in concertwith other components.

Additives (FCAs)

Co-processing of carrier particles with low surface energy materials isa further alternative for increasing the aerosolisation efficiencies ofdry powder inhaler formulations.

The primary role of these low surface energy materials is to modify theinterfacial properties of the carrier particles to decrease drug-carrieradhesion. Also known as Force Control Agents (“FCA”) these low surfaceenergy materials include amino acids, phospholipids or fatty acidderivatives such as stearates, particularly magnesium stearate.

Magnesium stearate continues to be used as a tableting aide because ofthe stearate's glidant properties. Magnesium stearate has also been usedto improve aerosol performance (Vectura), to improve resistance tomoisture ingress into a formulation (Skyepharma) and to improveresistance to active degradation (Chiesi) by preventing contact withmoisture.

Magnesium stearate's use in inhalable formulations leads to a generalimprovement in the fine particle fraction. This improvement in theinhalable fine particle fraction through the use of magnesium stearateenhances the dosing efficiency to the patient of the dry powderformulations administered by pulmonary inhalation due to an improvementof powder flowability from the dosing receptacle to the patient.

WO 2011 067212 discloses a pharmaceutical grade magnesium stearate,sourced from Peter Greven, complying with the requirements ofPh.Eur/USNF may be used as supplied with a mass median particle size of8 to 12 μm.

WO 2011 067212 discloses magnesium stearate in a composition in anamount of about 0.2 to 2%, e.g. 0.6 to 2% or 0.5 to 1.75%, e.g. 0.6%,0.75%, 1%, 1.25% or 1.5% w/w, based on the total weight of thecomposition. The magnesium stearate will typically have a particle sizein the range 1 to 50 μm, and more particularly 1-20 μm, e.g. 1-10 μm.Commercial sources of magnesium stearate include Peter Greven,Covidien/Mallinckodt and FACI.

WO 87/05213 describes a carrier, comprising a conglomerate of a solidwater-soluble carrier and a lubricant, preferably magnesium stearate,for improving the technological properties of the powder in such a wayas to remedy to the reproducibility problems encountered after therepeated use of a high resistance inhaler device. This teaching focusesexclusively on the ability of magnesium stearate to lubricate theinhaler components.

WO 1996 23485 discloses carrier particles which are mixed with ananti-adherent or anti-friction material consisting of one or morecompounds selected from amino acids (preferably leucine); phospholipidsor surfactants; the amount of additive and the process of mixing arepreferably chosen in such a way as to not give rise to a coating. It isstated that the presence of a discontinuous covering as opposed to a“coating” is an important and advantageous feature. The carrierparticles blended with the additive are preferably subjected to theprocess disclosed in WO 1995 011666.

WO 2000 028979 describes the use of small amounts of magnesium stearatefor improving stability to humidity of dry powder formulations forinhalation.

WO 2000 033789 describes an excipient powder for inhalable drugscomprising a coarse first fraction, a fine second fraction, and aternary agent which may be leucine.

Kassem (London University Thesis 1990) discloses the use of relativelyhigh amount of magnesium stearate (1.5%) for increasing the ‘respirable’fraction. However, the reported amount is too great and reduces themechanical stability of the mixture before use.

Glidants

The role of the tabletting glidant is to improve the flowability of thepowder. This is especially important during high speed tabletingproduction. The requirement of adequate powder flow necessitates the useof a glidant to the powder before tableting. Traditionally, talc (1-2%by weight) has been used as a glidant in tablet formulations. The mostcommonly used tableting glidant is colloidal silica (about 0.2% byweight) which has very small particles that adhere to the surfaces ofthe other ingredients and improve flow by reducing interparticulatefriction. Magnesium stearate, normally used as a tableting lubricant,can also promote powder flow of the tableting powder at lowconcentrations (<1% by weight). Concentrations above 1% by weight tendto adversely affect powder flow performance.

Lubricants

The function of the tableting lubricant is to ensure that tabletformation and ejection can occur with low friction between the solid andthe die wall. High friction during tableting can cause a series ofproblems, including inadequate tablet quality and may even stopproduction. Lubricants are thus included in almost all tabletformulations.

Tableting lubrication is achieved by either fluid lubrication orboundary lubrication. In fluid lubrication a layer of fluid (e.g. liquidparaffin) is located between the particles and die wall and thus reducesthe friction.

Boundary lubrication is a surface phenomenon because the slidingsurfaces are separated by a thin film of lubricant. The nature of thesolid surfaces will therefore affect friction. All substances that canaffect interaction between sliding surfaces can be described as boundarylubricants and in the case of tableting, they are fine particulatesolids.

A number of mechanisms have been discussed for these boundarylubricants. The most effective tableting tablet boundary lubricant ismagnesium stearate because of its properties. The stearic acid salts,including magnesium stearate, are normally used at low concentrations(<1% by weight) in tablet manufacture.

Besides reducing friction, lubricants may cause undesirable changes inthe properties of the tablet. The presence of a lubricant in a powder isthought to interfere in a deleterious way with the bonding between theparticles during compaction, and thus reduce tablet strength. Similarly,lubricants cause undesirable changes in inhaled formulations, especiallywith respect to reducing the desired adherence of the drug to thecarrier particle. These negative effects are strongly related to theamount of lubricant present, and a minimum amount is normally used in aformulation, i.e. concentrations of 1% or below. In addition, the way inwhich the lubricant is mixed with the other ingredients should also beconsidered. The sequence, total mixing time and the mixing intensity arealso important criteria.

Anti Adherent

An antiadherent reduces the adhesion between the powder and the punchfaces thereby preventing particles sticking to the tableting punch.Sticking or picking is the phenomenon whereby powders are prone toadhere to the punch. This problem is associated with the moisturecontent of the powder; higher moisture levels aggravate the problem. Theoccurrence is also aggravated if the punches are engraved or embossed.Many lubricants, such as magnesium stearate, have also antiadherentproperties. However, other substances with limited ability to reducefriction can also act as antiadherents, such as talc and starch.

Agglomerations

A further method of improving the flowing properties of cohesive powdersis to agglomerate, in a controlled manner, the micronised particles toform spheres of relatively high density and compactness. The process istermed spheronisation while the particles formed are called pellets. Theactive ingredient is mixed with a plurality of fine particles of one ormore excipients; the resulting product is called a soft pellet.

Generally, flow of compositions comprising fine carrier particles ispoor unless they are pelletised (e.g. AstraZeneca's product OXIS(registered trademark). However pelletisation has its own disadvantagesincluding being difficult to perform and produces variable Fine ParticleFractions (“FPF”).

The flow properties of the formulation can also be improved bycontrolled agglomeration of the powder. WO 2004 0117918 discloses amethod of preparing a dry powder inhalation composition comprising apharmaceutically acceptable particulate carrier, a first particulateinhalant medicament and a second particulate inhalant medicament. Thisapplication places particular importance in ensuring that any aggregatesof the micronized active are broken up and the active ingredient wasevenly distributed over the lactose carrier.

U.S. Pat. No. 5,518,998 discloses a therapeutic preparation comprisingactive compounds and a substance which enhances the absorption of theactive in the lower respiratory tract, the preparation is in the form ofa agglomerated dry powder suitable for inhalation.

GB 1,569,911 discloses the use of a binder to agglomerate a drug intosoft pellets, which is extruded through a sieve to create agglomerates.The formation of soft pellets allows carrier particles to be omittedfrom the composition. U.S. Pat. No. 4,161,516 also discloses theformation of soft drug pellets to improve powder flow. U.S. Pat. No.6,371,171 discloses spheronised agglomerates that are able to withstandprocessing and packaging but de-agglomerate into primary particlesduring inhalation.

EP 441740 discloses a process and apparatus for agglomerating andmetering non-flowable powders preferably constituted of micronisedformoterol fumarate and fine particles of lactose (soft pellets).Furthermore several methods of the prior art were generally addressed atimproving the flowability of powders for inhalation and/or reducing theadhesion between the drug particles and the carrier particles.

GB 1 242 211, GB 1 381 872 and GB 1 571 629 disclose pharmaceuticalpowders for the inhalation in which the micronised drug (0.01-10 μm) isrespectively mixed with carrier particles of sizes 30 to 80 μm, 80 to150 μm, and less than 400 μm wherein at least 50% by weight of which isabove 30 μm.

The prior art discloses several approaches for improving the flowabilityproperties and the respiratory performances of low strength activeingredients. WO 1998 031353 claims a dry powder composition comprisingformoterol and a carrier substance, both of which are in finely dividedform wherein the formulation has a poured bulk density of from 0.28 to0.38 g/ml. Said formulation is in the form of soft pellet and does notcontain any additive.

Whilst the matter of improved aerosol performance appears has beenadequately addressed by industry. There is still, however, a need forinhalable powders having improved dispersion of the API whilstmaintaining superior handling and powder flow characteristics.

Poorly Flowing Powders

In multidose DPIs, cohesive/adhesive particulates impair the loading ofthe powder from a chamber, thereby creating handling and meteringproblems.

Poor flowability is also detrimental to the respirable fraction of thedelivered dose because the active particles are unable to leave theinhaler. The active particles in a poor flowing powder are eitheradhered to the interior of the inhaler and/or they leave the inhaler aslarge agglomerates. Agglomerated particles generally cannot reach thebronchiolar and alveolar sites of the lungs because they are too largeand impact in the oralpharyngeal cavity or upper airways. The extent ofparticulate agglomeration between each actuation of the inhaler and alsobetween inhalers and different batches of particles, leads to poor dosereproducibility making these products unsuitable for patient use.

In this regard, it is well known that the interparticulate forces may betoo high and prevent the separation of the micronised drug particlesfrom the surface of the coarse carrier during inhalation. The surface ofthe carrier particles is, indeed, not smooth but has asperities andclefts, which are high energy sites on which the active particles arepreferably attracted to and adhere more strongly.

In consideration of all problems and disadvantages associated withrespect to the use of fine lactose, it would be highly advantageous toprovide a formulation capable of delivering active ingredients using aDPI device that has excellent flowability.

The Carr index is used in pharmaceutics as a powder flow indicator. ACarr index greater than 25 is considered to be an indication of poorlyflowing powder, and below 15, of acceptable flowability.

The Carr index is related to the Hausner ratio, another indication offlowability.

Packaging Lines

The efficiency and profitability of an inhaled product depends on thetype of pack and the material selected for the chosen production line.For example, the filling speed for an inhaled formulation will depend onits characteristics: the dosing size, flowability, the propensity of theformulation to segregate, as well as the receptacle into which thepowder will be dispensed. For a non-fragile easy-flowing powder, fillingspeeds for capsules are normally less than 300 000 doses per hour, with3000 doses per minute for a blister strip (assuming 60 doses per stripand 50 strips per minute) and approximately 3000 doses per minute for ablister pack. Choosing a poorly flowing powder irrespective of thereceptacle used could reduce the filling speed to well below thesevalues, severely impacting on the commercial success.

Tablets and inhaled formulations require the ability to be confined intoa predetermined space i.e. the filling machine. Tableting, however,requires that the dosage form remain intact and compact followingpressing and dispensing into the receptacle. Inhalation, in contrast,presents a completely different technical challenge in that the dosageform is required to withstand a small amount of compaction to assistdispensing of the powder plug from the filling apparatus into thereceptacle. Following dispensing into a receptacle this plug must thendisintegrate otherwise the powder is not presented in an inhalable form.This dosage form elasticity required by inhaled formulations presents asignificant challenge not yet solved in the art, especially when higherfines contents are used.

Acceptable aerosol performance is a crucial parameter for an inhaledformulations and a parameter that is routinely focused on byformulators. However, a formulation that does not readily andreproducible fill into a receptacle does not constitute commerciallyviable product.

In none of aforementioned documents have the features of the inventionbeen disclosed nor do any of them contemplate the problem or contributeor to the solution of the problem according to the invention.

All the attempts at obtaining stable powder formulations with lowstrength active ingredients endowed with good flowability and high fineparticle fraction according to the teaching of the prior art wereunsuccessful as demonstrated by either the prior art or the controlexamples reported below. In particular, the prior art reports that theproposed solutions for a technical problem (i.e. improving dispersion ofthe drug particles) was detrimental to other parameters (e.g. improvingflowability, mechanical stability) or vice versa.

SUMMARY OF THE INVENTION

The formulation of the invention shows excellent powder flow propertiesand physical stability combined with good performances in terms of fineparticle fraction of more than 15%, more than 20%, more than 30%, morethan 40% or preferably more than 50%.

It has been found that, unlike formulations containing conventionalcarriers with fine particle contents of above 10% which tend to havepoor flow properties, the formulations according to an embodiment of theinvention have excellent flow properties even with a fines content (thatis contents of active particles and fine excipient particles) of up to40%, preferably up to 50%, preferably up to 60%, preferably up to 70% byweight of the total formulation.

The fines content of the active and fine excipient material can bedetermined by laser diffraction particle size analysis, for example aSpraytec with Inhalation Cell, Malvern Instruments, Malvern, UK. Fineparticles (“Fines”) are characterized as particles with a D₁₀ below 5μm, D₅₀ below 15 μm and D₉₀ below 32 μm as determined by laserdiffraction particle size analysis, elucidation of what percentage ofthe fine fraction is contributed by the excipient, active or additive isnot required. The total amount of fines is of primary concern not theconstituent parts in this fine fraction. Using this methodology, thefine material may be easily determined in a formulation containinglarger carrier particles.

In one embodiment the active is a micronised active.

The phrase “originally exhibited” means the same powder without either astearate, or without magnesium stearate, or without calcium stearate orwithout sodium stearate, as the statement or claim so requires.

In one aspect the use of a stearate for improving the powder flowproperties of an inhaled formulation is disclosed, wherein the inhaledformulation comprises greater than 10% (w/w) fines content wherein thepowder flow property is improved as compared with the powder floworiginally exhibited. The improved powder flow characteristics make thepowder more amenable for use in an automated filling apparatus asdemonstrated by a reduction in the variation of the dosing range of adispensed inhalable formulation.

In one aspect the use of a stearate for improving the powder flowproperties of an inhaled formulation is disclosed, wherein the inhaledformulation comprises greater than 10% (w/w) fines content wherein thepowder flow property is improved as compared with the powder floworiginally exhibited. The improved powder flow characteristics make thepowder more amenable for use in an automated filling apparatus asdemonstrated by an improvement in the accuracy of the dosing of thedispensed formulation of the inhalable formulation.

In one aspect the use of a stearate for improving the powder flowproperties of an inhaled formulation is disclosed, wherein the inhaledformulation comprises greater than 10% (w/w) fines content wherein thepowder flow property is improved as compared with the powder floworiginally exhibited. The improved powder flow characteristics make thepowder more amenable for use in an automated filling apparatus asdemonstrated by an improvement in the precision of the dosing of thedispensed formulation of the inhalable formulation.

In one aspect the use of a stearate for improving the powder flowproperties of an inhaled formulation is disclosed, wherein the inhaledformulation comprises greater than 10% (w/w) fines content wherein thepowder flow property is improved as compared with the powder floworiginally exhibited, wherein the stearate is selected from magnesiumstearate, calcium stearate and/or sodium stearate. The improved powderflow characteristics make the powder more amenable for use in anautomated filling apparatus as demonstrated by a reduction in thevariation of the dosing range of a dispensed inhalable formulation.

In one aspect the use of magnesium stearate for improving the powderflow properties of an inhaled formulation comprising greater than 10%(w/w) fines content is disclosed wherein the powder flow property isimproved as compared with the powder flow originally exhibited. Theimproved powder flow characteristics make the powder more amenable foruse in an automated filling apparatus as demonstrated by a reduction inthe variation of the dosing range of a dispensed inhalable formulation.

In one aspect the use of magnesium stearate for improving the powderflow properties of an inhaled formulation is disclosed, wherein theformulation comprises greater than 10% (w/w) fines content and whereinthe powder flow property is improved as compared with the powder floworiginally exhibited wherein the magnesium stearate is present in anamount of from 0.01% to 50% by weight of the formulation. The improvedpowder flow characteristics make the powder more amenable for use in anautomated filling apparatus as demonstrated by a reduction in thevariation of the dosing range of a dispensed inhalable formulation.

In one aspect the use of magnesium stearate for improving the powderflow properties of an inhaled formulation is disclosed, wherein theformulation comprises greater than 10% (w/w) fines content wherein thepowder flow property is improved as compared with the powder floworiginally exhibited wherein the magnesium stearate is present in anamount of from 0.01% to 45% by weight of the formulation. The improvedpowder flow characteristics make the powder more amenable for use in anautomated filling apparatus as demonstrated by a reduction in thevariation of the dosing range of a dispensed inhalable formulation.

In one aspect the use of magnesium stearate for improving the powderflow properties of an inhaled formulation is disclosed, wherein theformulation comprises greater than 10% (w/w) fines content wherein thepowder flow property is improved as compared with the powder floworiginally exhibited wherein the magnesium stearate is present in anamount of from 0.01% to 40% by weight of the formulation. The improvedpowder flow characteristics make the powder more amenable for use in anautomated filling apparatus as demonstrated by a reduction in thevariation of the dosing range of a dispensed inhalable formulation.

In one aspect the use of magnesium stearate for improving the powderflow properties of an inhaled formulation is disclosed, wherein theformulation comprises greater than 10% (w/w) fines content wherein thepowder flow property is improved as compared with the powder floworiginally exhibited wherein the magnesium stearate is present in anamount of from 0.01% to 30% by weight of the formulation. The improvedpowder flow characteristics make the powder more amenable for use in anautomated filling apparatus as demonstrated by a reduction in thevariation of the dosing range of a dispensed inhalable formulation.

In one aspect the use of magnesium stearate for improving the powderflow properties of an inhaled formulation is disclosed, wherein theformulation comprises greater than 10% (w/w) fines content wherein thepowder flow property is improved as compared with the powder floworiginally exhibited wherein the magnesium stearate is present in anamount of from 0.01% to 20% by weight of the formulation. The improvedpowder flow characteristics make the powder more amenable for use in anautomated filling apparatus as demonstrated by a reduction in thevariation of the dosing range of a dispensed inhalable formulation.

In one aspect the use of magnesium stearate for improving the powderflow properties of an inhaled formulation is disclosed, wherein theformulation comprises greater than 10% (w/w) fines content wherein thepowder flow property is improved as compared with the powder floworiginally exhibited wherein the magnesium stearate is present in anamount of from 0.01% to 10% by weight of the formulation. The improvedpowder flow characteristics make the powder more amenable for use in anautomated filling apparatus as demonstrated by a reduction in thevariation of the dosing range of a dispensed inhalable formulation.

In one aspect the use of magnesium stearate for improving the powderflow properties of an inhaled formulation is disclosed, wherein theformulation comprises greater than 10% (w/w) fines content wherein thepowder flow property is improved as compared with the powder floworiginally exhibited wherein the magnesium stearate is present in anamount of from 0.01% to 5% by weight of the formulation. The improvedpowder flow characteristics make the powder more amenable for use in anautomated filling apparatus as demonstrated by a reduction in thevariation of the dosing range of a dispensed inhalable formulation.

In one aspect the use of magnesium stearate for improving the powderflow properties of an inhaled formulation is disclosed, wherein theformulation comprises greater than 10% (w/w) fines content wherein thepowder flow property is improved as compared with the powder floworiginally exhibited wherein the magnesium stearate is present in anamount of from 0.1% to 2% by weight of the formulation. The improvedpowder flow characteristics make the powder more amenable for use in anautomated filling apparatus as demonstrated by a reduction in thevariation of the dosing range of a dispensed inhalable formulation.

In one aspect a method for improving the powder flow characteristics ofa pharmaceutical formulation making the powder more amenable for use inan automated filling apparatus is disclosed, as demonstrated by areduction in the variation of the dosing range of the dispensedformulation. The method comprising the addition of magnesium stearate tothe pharmaceutical formulation. The pharmaceutical formulationcomprising greater than 10% (w/w) fines content.

In one aspect a method for improving the powder flow characteristics ofan inhaled pharmaceutical formulation making the powder more amenablefor use in an automated filling apparatus is disclosed, as demonstratedby a reduction in the variation of the dosing range of the dispensedinhalable formulation. The method comprising the addition of magnesiumstearate to the pharmaceutical formulation. The inhaled pharmaceuticalformulation comprising greater than 10% (w/w) fines content.

In one aspect a method of processing an inhaled pharmaceuticalformulation, the method comprising addition of magnesium stearate to thepharmaceutical formulation is disclosed, thereby improving the powderflow characteristics making the powder more amenable for use in anautomated filling apparatus as demonstrated by a reduction in thevariation of the dosing range of a dispensed inhalable formulation.

In one aspect a method for improving the powder flow characteristics ofa pharmaceutical formulation making the powder more amenable for use inan automated filling apparatus is disclosed, as demonstrated by animprovement in the accuracy of the dosing of the dispensed formulation.The method comprising the addition of magnesium stearate in thepharmaceutical formulation. The pharmaceutical formulation comprisinggreater than 10% (w/w) fines content.

In one aspect a method for improving the powder flow characteristics ofan inhaled pharmaceutical formulation making the powder more amenablefor use in an automated filling apparatus is disclosed, as demonstratedby an improvement in the accuracy of the dosing of the dispensedinhalable formulation. The method comprising the addition of magnesiumstearate in the pharmaceutical formulation. The inhaled pharmaceuticalformulation comprising greater than 10% (w/w) fines content.

In one aspect a method of processing an inhaled pharmaceuticalformulation, the method comprising addition of magnesium stearate to thepharmaceutical formulation thereby improving the powder flowcharacteristics making the powder more amenable for use in an automatedfilling apparatus is disclosed, as demonstrated by an improvement in theaccuracy of the dosing of a dispensed inhalable formulation.

In one aspect a method for improving the powder flow characteristics ofa pharmaceutical formulation is disclosed by making the powder moreamenable for use in an automated filling apparatus as demonstrated by animprovement in the precision of the dosing of the dispensed formulation.The method comprising the addition of magnesium stearate in thepharmaceutical formulation. The pharmaceutical formulation comprisinggreater than 10% (w/w) fines content.

In one aspect a method for improving the powder flow characteristics ofan inhaled pharmaceutical formulation is disclosed by making the powdermore amenable for use in an automated filling apparatus as demonstratedby an improvement in the precision of the dosing of the dispensedinhalable formulation. The method comprising the addition of magnesiumstearate in the pharmaceutical formulation. The inhaled pharmaceuticalformulation comprising greater than 10% (w/w) fines content.

In one aspect a method of processing an inhaled pharmaceuticalformulation is disclosed, the method comprising the addition ofmagnesium stearate to the pharmaceutical formulation thereby improvingthe powder flow characteristics making the powder more amenable for usein an automated filling apparatus as demonstrated by an improvement inthe precision of the dosing of a dispensed inhalable formulation.

In one aspect a method for improving the powder flow characteristics ofa pharmaceutical formulation is disclosed, the method making the powdermore amenable for use in an automated filling apparatus as demonstratedby a reduction in the variation of the dosing range of the dispensedformulation, and demonstrated by an improvement in the accuracy of thedosing of the dispensed formulation and demonstrated by an improvementin the precision of the dosing of the dispensed formulation. The methodcomprising the addition of magnesium stearate in the pharmaceuticalformulation. The pharmaceutical formulation comprising greater than 10%(w/w) fines content.

In one aspect a method for improving the powder flow characteristics ofan inhaled pharmaceutical formulation making the powder more amenablefor use in an automated filling apparatus is disclosed, as demonstratedby a reduction in the variation of the dosing range of the dispensedinhalable formulation, and demonstrated by an improvement in theaccuracy of the dosing of the dispensed inhalable formulation anddemonstrated by an improvement in the precision of the dosing of thedispensed inhalable formulation. The method comprising the addition ofmagnesium stearate in the pharmaceutical formulation. The inhaledpharmaceutical formulation comprising greater than 10% (w/w) finescontent.

In one aspect a method of processing an inhaled pharmaceuticalformulation, the method comprising submitting the inhaled pharmaceuticalformulation to compression and shearing forces in the presence ofmagnesium stearate to improve the powder flow characteristics isdisclosed thereby making the powder more amenable to use in an automatedfilling apparatus as demonstrated by a reduction in the variation of thedosing range of a dispensed inhalable formulation.

In one aspect a method of processing an inhaled pharmaceuticalformulation is disclosed, the method comprising submitting the inhaledpharmaceutical formulation to compression and shearing forces in thepresence of magnesium stearate thereby improving the powder handlingcharacteristics as demonstrated by a reduction in the variation of thedosing range of the dispensed inhalable formulation, wherein thepharmaceutical formulation has a fines content of greater than 5%,greater than 10%, greater than 15%, greater than 20%, greater than 25%,greater than 30%, greater than 35%, greater than 40%, greater than 45%or greater than 50% by weight of the total dispensed formulation asdetermined by particle size analysis.

A dispensed formulation is the formulation found within a receptacle.

In one embodiment, the cohesiveness between the particles is adjusted insuch a way to give sufficient adhesion force to hold the activeparticles to the surface of the carrier particles during manufacturingof the dry powder and in the delivery device before use, but alsoenables the effective and reproducible filling of powder intoreceptacles to be incorporated into inhalation devices.

In one aspect a pharmaceutical formulation obtainable or obtained usingthe above method is disclosed.

In one aspect an inhaler device comprising a pharmaceutical formulationobtainable or obtained by the method of the invention, or apharmaceutical formulation which has been further processed wherenecessary into a suitable pharmaceutically acceptable form is disclosed.

In one aspect a receptacle, such as a blister, capsule or reservoir,comprising a pharmaceutical formulation, obtainable or obtained by themethod of the invention, or an active ingredient which has been furtherprocessed where necessary into a suitable pharmaceutically acceptableform is disclosed.

In one aspect a powder inhaler is disclosed having a reservoir (alsoconsidered a receptacle along with blisters, capsules, blister packs andblister strips), the finished pharmaceutically preparation is filledinto the reservoir in the form of a powder bed. A dose is withdrawn bymeans of a suitably designed dosage device. Withdrawal takes placeeither volumetrically or gravimetrically. The accurate dosage of thepreparation for most active compounds necessitates dilution with apharmaceutically inactive excipient in order to obtain a measurable unitamount accurately meeting the dosage demands.

In one aspect a method is disclosed for producing an inhaledpharmaceutical formulation, the method comprising addition of magnesiumstearate to the pharmaceutical formulation thereby ameliorating thecohesive effect of fine particles and improving the powder handlingperformance.

In one aspect a method is disclosed for producing an inhaledpharmaceutical formulation, the method comprising addition of magnesiumstearate separately to the formulation's constituent components therebyameliorating the cohesive effect of fine particles and improving thepowder handling performance.

In one aspect a method is disclosed for producing an inhaledpharmaceutical formulation, the method comprising addition of magnesiumstearate separately to another constituent components of the formulationbefore addition of other formulation constituents thereby amelioratingthe cohesive effect of fine particles and improving the powder handlingperformance.

In one aspect the powder compositions produced may preferably have atapped density of more than 0.1 g/cc, more than 0.2 g/cc, more than 0.3g/cc, more than 0.4 g/cc, more than 0.5 g/cc, more than 0.6 g/cc orpreferably more than 0.7 g/cc.

In one aspect the use of a stearate for improving powder flow andaerosol properties of an inhaled formulation wherein the powder flow andaerosol properties are improved as compared with the powder flow andaerosol properties originally exhibited is disclosed, wherein thestearate is selected from magnesium stearate, calcium stearate and/orsodium stearate and wherein magnesium stearate is especially preferred.

In one aspect the use of a stearate for the amelioration of the cohesiveeffect of fine particles in an inhaled formulation wherein the powderflow properties are improved over the powder flow originally exhibitedis disclosed, wherein the formulation fines content is greater than 10%,greater than 15%, greater than 20% or greater than 25% by weight of theformulation as determined by particle size analysis, wherein thestearate is selected from magnesium stearate, calcium stearate and/orsodium stearate, wherein magnesium stearate is especially preferred.

In one aspect a method of dispensing a predetermined amount of aninhalable formulation from an automated powder filling apparatus, themethod comprising storing the inhalable formulation comprising magnesiumstearate in an amount of from 0.1 to 2.0% by weight of the formulationin a powder hopper, flowing an amount of inhalable formulation from thehopper into a dosing aperture to create a predetermined amount ofinhalable formulation, moving the predetermined amount of inhalableformulation within the dosing aperture from a first position to a secondposition and releasing the predetermined amount of inhalable formulationfrom the dosing aperture so as to dispense the predetermined amount ofinhalable formulation therein with improved dosing reproducibility, isdisclosed.

In one aspect a method of improving the dispensed dosing reproducibilityof an inhalable formulation from an automated powder filling apparatuscomprising storing the inhalable formulation comprising magnesiumstearate in an amount of from 0.1 to 2.0% by weight of the formulationin a powder hopper, flowing an amount of inhalable formulation from thehopper into a dosing aperture to create a predetermined amount ofinhalable formulation, moving the predetermined amount of inhalableformulation within the dosing aperture from a first position to a secondposition and releasing the predetermined amount of inhalable formulationfrom the dosing aperture so as to dispense the predetermined amount ofinhalable formulation, is disclosed.

In one aspect an automated powder filling apparatus, for example, HarroHofliger's Omnidose automated powder filling apparatus and 3Pi's Dosatorvolumetric filling apparatus are disclosed in combination with allparagraphs disclosed in the summary of the invention.

Formulation Manufacture

The ability to balance the natural cohesion possessed by APT and thecohesion contributed by the remaining formulation constituents is acrucial parameter for working the invention.

In view of the present disclosure, the skilled person will now be ableto quickly assess the cohesion exhibited by the active particles and theremaining formulation constituents and produce an inhalable formulationwith excellent powder handling characteristics despite an elevated levelof fine particles.

The following processes, which are not limiting, are suitable to workthe invention.

Milling

The process of milling may also be used to formulate the dry powdercompositions according to the present invention. The manufacture of fineparticles by milling can be achieved using conventional techniques. Inthe conventional use of the word, “milling” means the use of anymechanical process which applies sufficient force to the particles ofactive or excipient or additive material that it is capable of (notnecessarily does) breaking coarse particles (for example, particles witha D50 greater than 100 μm) down to fine particles (for example, having aD50 not more than 50 μm) as determined by laser diffraction particlesize analysis, for example a Spraytec with Inhalation Cell, MalvernInstruments, Malvern, UK. In the present invention, the term “milling”also refers to deagglomeration of particles in a formulation, with orwithout particle size reduction. The particles being milled may be largeor fine prior to the milling step. A wide range of milling devices andconditions are suitable for use in the production of the compositions ofthe inventions. The selection of appropriate milling conditions, forexample, intensity of milling and duration, to provide the requireddegree of force will be within the ability of the skilled person.

The process of milling may also be used to formulate the dry powdercompositions according to the present invention. The manufacture of fineparticles by milling can be achieved using conventional techniquesmentioned below and in the examples.

According to one embodiment of the invention, the active agent is milledwith a force control agent and/or with an excipient material which candelay or control the release of the active agent when the activeparticles of the invention are deposited in the lung. Co-milling orco-micronising particles of active agent and particles of FCA orexcipient will result in the FCA or excipient becoming deformed andbeing smeared over or fused to the surfaces of fine active particles.

According to one embodiment of the invention the resultant compositeactive particles comprising magnesium stearate have been found to beless cohesive after the milling treatment as determined by tappeddensity when compared with a sample of the active particles prior toprocessing with magnesium stearate.

The milling processes preferably apply a sufficient degree of force tobreak up tightly bound agglomerates of fine or ultra-fine particles,such that effective mixing and effective application of the additivematerial to the surfaces of those particles is achieved.

The additive material is preferably in the form of a coating on thesurfaces of the particles of active material. The coating may be adiscontinuous coating. The additive material may be in the form ofparticles adhering to the surfaces of the particles of active material.

At least some of the composite active particles may be in the form ofagglomerates. However, when the composite active particles are includedin a pharmaceutical composition, the additive material promotes thedispersal of the composite active particles on administration of thatcomposition to a patient, via actuation of an inhaler. The termcomposite active particle describes a particle of active materialcompletely covered or partially covered with a separate particle ofadditive material. The particle of additive material has undergone aprocess of deformation during the construction of the composite activeparticle. The term composite active particle does not describe aparticle of active abutting a particle of additive; there must be adegree of deformation imparted to the particle of additive material.Composite active particles are typically created when the activeparticle is harder than the particle of additive material. This may bedetermined by visual inspection; the active material is eithercompletely covered or partially covered with a separate particle ofdeformed additive material.

The following specific processes, which are not limiting, are suitableto work the invention.

In one aspect processing of an active alone indicates processing in theabsence of other materials that might be suitable for inclusion in apharmaceutical product. For example, processing is carried out in theabsence of an excipient. The invention relates, in one particularaspect, to a method of processing an active ingredient, the methodcomprising submitting an active ingredient or ingredients alone tocompression and shearing forces in the absence of magnesium stearateuntil processing of the active material is completed before magnesiumstearate is combined with the ingredients.

Mechanofusion

Mechanofusion has previously been described as a dry process designed tomechanically fuse a first material onto a second material. It should benoted that the use of the terms “mechanofusion” and “mechanofused” aresupposed to be interpreted as a reference to a particular type ofmilling process, but not a milling process performed in a particularapparatus. The compressive milling processes work according to adifferent principle to other milling techniques (“comminutiontechniques”), relying on a particular interaction between an innerelement and a vessel wall, and they are based on providing energy by acontrolled and substantial compressive force.

The active ingredient is fed into the vessel of a mechanofusionapparatus (such as a Mechano-Fusion system (Hosokawa Micron Ltd)) or theNobilta (Hosokawa Micron Ltd) or Nanocular (Hosokawa Micron Ltd)apparatus, where it is subject to a centrifugal force and is pressedagainst the vessel inner wall. The active ingredient is compressedbetween the fixed clearance of the drum wall and a curved inner elementwith high relative speed between drum and element. The inner wall andthe curved element together form a gap or nip in which the particles arepressed together. As a result, the active ingredient experiences veryhigh shear forces and very strong compressive stresses as they aretrapped between the inner drum wall and the inner element (which has agreater curvature than the inner drum wall). The particles are pressedagainst each other with enough energy to locally increase thetemperature and soften, break, distort, flatten and thereby reduce theamount of amorphous/disordered material in the sample.

Either the outer vessel or the inner element may rotate to provide therelative movement. In an alternate embodiment the outer vessel and theinner element may rotate in opposite directions with respect to eachother.

The gap between the outer vessel and the inner element surfaces isrelatively small, and is typically less than 10 mm and is preferablyless than 5 mm, more preferably less than 3 mm, more preferably lessthan 2 mm, preferably less than 1 mm or preferably less than 0.5 mm.This gap is fixed, and consequently leads to a better control of thecompressive energy than is provided in some other forms of mill such asball and media mills. Alternatively, a sequential use of rotors withsmaller gaps throughout the blending process may be used. Such anapproach lends itself to providing control over initial powderprocessing permitting gentler forces before using rotors with smallergaps to impart a milling process of greater intensity. A sequential useof different rotor speeds may be used throughout the blending process.Such an approach lends itself to providing control over initial powderprocessing (i.e. deagglomeration) permitting gentler forces before usinghigher rotor speeds to impart a milling process of greater intensity.

The speed of rotation may vary between the ranges of 200 to 10,000 rpmthroughout processing. Typical processing capacity is between 4000-5000rpm, which equates to 80% engine capacity.

It is, however, preferable to introduce powder into the processingchambers at slower speeds. Introduction of powder at slower speedsprevents clogging because it is easier to process an already movingpowder. A scraper may also be present to break up any caked materialbuilding up on the vessel surface. This is particularly advantageouswhen using fine cohesive starting materials.

The local temperature may be controlled by use of a heating/coolingjacked built into the drum vessel walls.

The above processes suitably apply a high enough degree of force toseparate individual particles of active ingredient and to break uptightly bound agglomerates of the active ingredient.

Cyclomix

Another compressive milling process that may be used in the presentinvention is the Cyclomix method. The Cyclomix comprises a stationaryconical vessel with a fast rotating shaft with paddles which move closeto the wall. Due to the high rotational speed of the paddles, the activeingredient is propelled towards the wall, and as a result it experiencesvery high shear forces and compressive stresses between wall and paddle.Such effects are similar to those in mechanofusion as described aboveand may be sufficient to increase the temperature and soften, to break,distort, and flatten the active ingredient particles.

The device used is preferably capable of exerting a force of greaterthan 1 N. It will be appreciated by the skilled person, that pressureforce that is exerted upon the active will be affected by multiplefactors including the force imparted by the rotor on the powder whencompressed against the drum wall, the volume of powder within theprocessing chamber, weight of the powder, density of the powder and theinherent cohesiveness of the powder components which dictate theresistance to flow. In addition to these, the speed, temperature,humidity, amount of powder and type of machine can be variedindependently to achieve a suitable form of an active according to thepresent invention.

Hybridiser®

In another aspect the compressive and shearing forces may be carried outby the Hybridiser® Method. The active ingredient is fed into theHybridiser. The powder is subjected to ultra-high speed impact,compression and shear as it is impacted by blades on a high speed rotorinside a stator vessel, and is re-circulated within the vessel. Typicalspeeds of rotation are in the range of 5,000 to 20,000 rpm.

Quadro® Comil®

Comills are capable of reducing solids to particle sizes in thelow-micron to submicron range. Traditionally, Comils have been used todeaggolmerate powders, specifically powders which are then subsequentlycombined into blending apparatuses. The grinding energy is created byrotating paddles/stirrers that rotate within close proximity to theconical sieve of the Comil®. Particles in the powder bed are forcedagainst the sieve of the Comil®, forcing the particles active materialover the particles of excipient material before the composite particlesare forced through the sieve. The interaction of the particles in thepowder bed create a violent sheer and as the particles abrade with oneanother.

In the past, the Comil® has not been considered attractive for millingactive and excipient particles, with controlled compressive processessimilar to Mechanical Chemical Bonding (mechanofusion) and cyclomixingbeing clearly preferred. The interaction between the particles in aComil® are somewhat uncontrolled and those skilled in the art,therefore, considered it unlikely for this technique to be able toprovide the desired deposition of a coating of active material on thesurface of the excipient particles because the residency time has beendifficult to control. Hence the reason for the preference of thisapparatus for use as a sieve rather than use this apparatus to forceactive particle to adhere to particle of excipient thereby creatingcomposite active particles and/or composite excipient particles.

According to the present invention, the powder components undergo acompressive formulation process. The compressive milling processes worksaccording to a different principle to the convention Comil® millingtechniques, relying on a particular interaction between an inner elementand a sieve wall, and they are based on providing energy by a controlledand substantial compressive force. The powder is compressed between thefixed clearance of the sieve wall and a curved inner element of theComil® paddle with high relative speed between sieve and paddle. Thesieve and the paddle together form a gap of predetermined width in whichthe particles are pressed together and the active or additive smearedover the excipient. The difference between this formulation process andthe mechanofusion process is the presence of the curved inner sieve. Theporosity of the sieve affords the formulation sufficient time foradequate blending before leaving the chamber to be collected. Thiscontinuous processing and collection beyond the chamber permits acontinuous process unlike the batch-type processes of the mechanofusionsystem. Furthermore the duration of mixing and resultant size of theparticles according to the invention can be modified through theselection of sieve size.

The process works particularly well where one of the materials isgenerally smaller and/or softer than the other. In one aspect the activeis harder than the additive allowing the additive distort and wraparound the active thereby creating a composite active particle. In oneaspect the excipient is harder than the additive allowing the additivedistort and wrap around the excipient thereby creating a compositeexcipient particle. When the presence of an additive material isrequired, an especially desirable aspect of the described process isthat additive material becomes deformed in the milling and may besmeared over or fused to the surfaces of the active particles to give auniform appearance.

In another embodiment, the particles produced using a jet-mill processmay subsequently undergo processing in a Comil®. This final Comil® stepis thought to “polish” the composite active particles (active andadditive) or excipient particles (excipient and additive), furtherrubbing the additive material onto and around the active or excipientparticles. This permits the beneficial properties normally afforded toparticles produced by mechanofusion but with the advantages of acontinuous manufacturing system.

The surprising effect is that a machine routinely used for sievingparticles can now be used to spread active over the surface of theexcipient and still dramatically improved the aerosolisation performanceof the manufactured formulation.

In one aspect, a process for preparing a dry powder pharmaceuticalcomposition is disclosed comprising the steps of pre-blendingformulation components until sufficient homogeneity and cohesion isachieved and then milling said pre-blend in a Quadro® Comil® until thefinal formulation possesses the desired respirable characteristicssuitable for administration by pulmonary inhalation.

Ball Milling

Ball milling is a milling method used in many of the prior artco-milling processes. Centrifugal and planetary ball milling may also beused.

Jet Mills and Co-Jet Milling

Jet mills are capable of reducing solids to particle sizes in thelow-micron to submicron range. The grinding energy is created by gasstreams from horizontal grinding air nozzles. Particles in the fluidisedbed created by the gas streams are accelerated towards the centre of themill, colliding within. The gas streams and the particles carried inthem create a violent turbulence and, as the particles collide with oneanother, they are pulverized.

High Pressure Homogenisers

High pressure homogenisers involve a fluid containing the particlesbeing forced through a valve at high pressure, producing conditions ofhigh shear and turbulence. Suitable homogenisers include EmulsiFlex highpressure homogenisers which are capable of pressures up to 4000 bar,Niro Soavi high pressure homogenisers (capable of pressures up to 2000bar) and Microfluidics Microfluidisers (maximum pressure 2750 bar).

TURBULA®

The mixing efficiency of the TURBULA is achieved by the interaction ofrotation, translation and inversion of the powder container. The TURBULAis considered to be low-shear blending process. This mixer istraditionally used for homogeneous mixing of powdered substances,specifically those with different specific weights and particle sizes.The mixing container turns in a three-dimensional motion and the productis subjected to an ever-changing, rhythmically pulsing motion. Theresults meet the highest requirements and are achieved in a minimum oftime

Diosna

Diosna type systems are often used to formulate lactose basedformulations and are considered to be high-shear blending processes. Infact the predominant formulation process in Diosna type systems is moreactive to excipient impaction rather than a shearing and smearing of theactive to the excipient.

Product Components

Traditionally, dry powder inhaler (“DPI”) devices contain particulateactive pharmaceutical ingredient (“API”) which is mixed with anexcipient powder of larger average particle size (“Carrier Particle”)and additive of varying particle size (“Additive”) to create ahomogenous formulation giving rise to so-called “ordered mixtures”. Insome cases, the additive may comprise a combination of materials,including fine carrier particles (“Lactose Fines”). These fine carrierparticles do not function as traditional carrier but instead moderatethe interaction of the active with the larger carrier particles byresting on or around the larger carrier. The larger particle size of thecarrier facilitates a flowable powder mixture. Furthermore thehomogeneity of the mixture enables metering into consistent doses.Obtaining an accurate and consistent dose is of particular importancewhen very small quantities of the cohesive drug are required.

API

Respirable particles are generally considered to be those with aparticle size distribution wherein D₁₀≤6 μm, D₅₀≤7 μm and D₉₀≤10 μm,particles within this distribution are capable of reaching into thebronchiolar and alveolar regions (“lower lung”) where the majority ofthe absorption takes place. Larger particles with a particle sizedistribution wherein D₁₀≥30 μm, D₅₀≥45 μm and D₉₀≥70 μm are mostlydeposited in the oralpharyngeal cavity so they cannot reach the lowerlung. The majority of the particles that are smaller than the respirablerange tend to be exhaled.

In particular formulations wherein D₉₀≥20 μm are substantially depositedin the oralpharyngeal cavity so they cannot reliably reach the lowerlung and are not considered suitable and safe as an inhalableformulation. Formulations wherein D₉₀≥20 μm are eminently suitable fororal delivery. Formulations comprising for example, D₅₀≥10 μm, mightpossess a lower range of particles considered an inhalable but theseformulations contain a substantial proportion of particles which are notsuitable for inhalation making the delivery inconsistent andconsequently unsafe from an inhalation perspective.

It is well known that particle impaction in the upper airways of asubject is predicted by the so-called impaction parameter. The impactionparameter is defined as the velocity of the particle multiplied by thesquare of its aerodynamic diameter. Consequently, the probabilityassociated with delivery of a particle through the upper airways regionto the target site of action, is related to the square of itsaerodynamic diameter. Therefore, delivery to the lower airways, or thedeep lung is dependent on the square of its aerodynamic diameter, andsmaller aerosol particles are very much more likely to reach the targetsite of administration in the user and therefore able to have thedesired therapeutic effect.

In one aspect of the invention the active ingredient may be micronisedprior to compression and shearing. Micronisation may be by any suitablemethod. Micronization is the process of reducing the average diameter ofparticles of a solid material, for example by milling or grinding.

In one aspect the active ingredient is in the form of particles prior toprocessing.

In one aspect reference to processing of an active ingredient aloneherein includes reference to processing of two or more actives alone,unless otherwise clear from the context.

In one aspect of the invention the composition is a dry powder which hasa fine particle fraction (<5 μm) of at least 30%, preferably at least40%, at least 50% or at least 60% when measured at 60 L/min using a NewGeneration Impactor (“NGI”) apparatus delivered from a Monohalerinhalation device.

Metered Dose/Nominal Dose

The metered dose (MD), also known as the Nominal Dose (ND), of a drypowder composition is the total mass of active agent present in themetered form presented by the inhaler device in question i.e. the amountof drug metered in the dosing receptacle or container. For example, theMD might be the mass of active agent present in a capsule for aCyclohaler™, or in a foil blister in a GyroHaler™ device or powderindentations of the frustoconical dispensing cone of a ClickHaler™.

The MD is different to the amount of drug that is delivered to thepatient (i.e. does that leave the inhaler device) which is referred to aDelivered Dose (DD) or Emitted Dose (ED). These terms are usedinterchangeably herein and they are measured as set out in the currentEP monograph for inhalation products.

Emitted Dose

The emitted dose (ED) is the total mass of the active agent emitted fromthe device following actuation. It does not include the material left onthe internal or external surfaces of the device, or in the meteringsystem including, for example, the capsule or blister. The ED ismeasured by collecting the total emitted mass from the device in anapparatus frequently identified as a dose uniformity sampling apparatus(DUSA), and recovering this by a validated quantitative wet chemicalassay (a gravimetric method is possible, but this is less precise).

Fine Particle Dose

The fine particle dose (FPD) is the total mass of active agent which isemitted from the device following actuation which is present in anaerodynamic particle size smaller than a defined limit. This limit isgenerally taken to be 5 μm if not expressly stated but an alternativelimit, such as 3 μm, 2 μm or 1 μm, etc may be used. The FPD is measuredusing an impactor or impinger, such as a twin stage impinger (TSI),multi-stage impinger (MSI), Andersen Cascade Impactor (ACI) or a NextGeneration Impactor (NGI). Each impactor or impinger has apre-determined aerodynamic particle size collection cut points for eachstage known to the person skilled in the art. The FPD value is obtainedby interpretation of the stage-by-stage active agent recovery quantifiedby a validated quantitative wet chemical assay (a gravimetric method ispossible, but this is less precise) where either a simple stage cut isused to determine FPD or a more complex mathematical interpolation ofthe stage-by-stage deposition is used.

Fine Particle Fraction

The fine particle fraction (FPF) is normally defined as the FPD (thedose that is <5 μm) divided by the Emitted Dose (ED) which is the dosethat leaves the device. The FPF is expressed as a percentage. Herein,the FPF of ED is referred to as FPF (ED) and is calculated as FPF(ED)=(FPD/ED)×100%.

The fine particle fraction (FPF) may also be defined as the FPD dividedby the Metered Dose (MD) which is the dose in the blister or capsule,and expressed as a percentage. Herein, the FPF of MD is referred to asFPF (MD), and may be calculated as FPF (MD)=(FPD/MD)×100%.

Fine Particle Mass

The fine particle mass (FPM) is the weight of medicament within a givendose that reaches the desired size airways to be effective.

Ultrafine Particle Dose

The term “ultrafine particle dose” (UFPD) is used herein to mean thetotal mass of active material delivered by a device which has a diameterof not more than 3 μm. The term “ultrafine particle fraction” is usedherein to mean the percentage of the total amount of active materialdelivered by a device which has a diameter of not more than 3 μm. Theterm percent ultrafine particle dose (% UFPD) is used herein to mean thepercentage of the total metered dose which is delivered with a diameterof not more than 3 μm (i.e., % UFPD=100×UFPD/total metered dose).

As used herein, the term “pharmaceutically acceptable esters” of activerefers to for example, those derived from pharmaceutically acceptablealiphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include formates, acetates, propionates, butryates,acrylates and ethyl succinates.

Additive Material

In one aspect of the present invention the additive may comprise a metalstearate, or a derivative thereof, for example, sodium stearyl fumarateor sodium stearyl lactylate. Advantageously, it comprises a metalstearate, for example, zinc stearate, magnesium stearate, calciumstearate, sodium stearate or lithium stearate. Preferably, the additivematerial comprises magnesium stearate, for example vegetable magnesiumstearate, or any form of commercially available metal stearate, whichmay be of vegetable or animal origin and may also contain other fattyacid components such as palmitates or oleates.

In one aspect the additive may include or consist of one or more surfaceactive materials. A surface active material may be a substance capablereducing the surface tension of a liquid in which it is dissolved.Surface active materials may in particular be materials that are surfaceactive in the solid state, which may be water soluble or waterdispersible, for example lecithin, in particular soya lecithin, orsubstantially water insoluble, for example solid state fatty acids suchas oleic acid, lauric acid, palmitic acid, stearic acid, erucic acid,behenic acid, or derivatives (such as esters and salts) thereof such asglyceryl behenate. Specific In one aspect the additive may includecholesterol.

In one aspect the additive may include sodium benzoate, hydrogenatedoils which are solid at room temperature, talc, titanium dioxide,aluminium dioxide, silicon dioxide and starch. Also useful as additivesare film-forming agents, fatty acids and their derivatives, as well aslipids and lipid-like materials.

In one aspect the additive particles may comprise lactose.

In one aspect the additive particles may comprise composite additiveparticles comprising lactose fines.

The additive lactose may be added a various stages of the formulationassembly or the additive lactose may be formed as a result of processingof a larger lactose carrier particle. Said processing produces smallerlactose particles that may adhere to the larger carrier particles orcombine with different components of the composition.

In one aspect a plurality of different additive materials can be used.

Carrier Particles

According the invention carrier particles may be of any acceptable inertexcipient material or combination of materials. For example, carrierparticles frequently used in the prior art may be composed of one ormore materials selected from sugar alcohols, polyols and crystallinesugars. Other suitable carriers include inorganic salts such as sodiumchloride and calcium carbonate, organic salts such as sodium lactate andother organic compounds such as polysaccharides and oligosaccharides.Advantageously, the carrier particles comprise a polyol. In particular,the carrier particles may be particles of crystalline sugar, for examplemannitol, dextrose or lactose. Preferably, the carrier particles arecomposed of lactose. Suitable examples of such excipient includeLactoHale 300 (Friesland Foods Domo), LactoHale 200 (Friesland FoodsDomo), LactoHale 100 (Friesland Foods Domo), PrismaLac 40 (Meggle),InhaLac 70 (Meggle).

In one aspect the ratio in which the carrier particles (if present) andactive ingredient are mixed will depend on the type of inhaler deviceused, the type of active particle used and the required dose. In oneaspect the carrier particles may be present in an amount of at least50%, more preferably 70%, advantageously 90% and most preferably 95%(w/w) based on the weight of the formulation.

In accordance with the present invention, the term “lactose” as usedherein is to be broadly construed. As an example, lactose is intended toencompass physical, crystalline, amorphous and polymorphic forms oflactose, including, but not limited to, the stereoisomers a-lactosemonohydrate and P-anhydrous lactose, as well as a-anhydrous lactose.Combinations of the above may be used.

In one aspect the for example a plurality of milled lactose particlesmay exist in at least two fractions having an average particle size(D₅₀) ranging from about 5-50 microns as well as a coarse fractionhaving an average particle size (D₅₀.) ranging from about 60-250microns, as measured by Malvern particle sizing.

In one aspect the compositions of the present invention comprise activeparticles, preferably comprising conditioned active, and carrierparticles. The carrier particles may have an average particle size offrom about 5 to about 1000 μm, from about 4 to about 40 μm, from about60 to about 200 μm, or from 150 to about 1000 μm as measured by Malvernparticle sizing. Other useful average particle sizes for carrierparticles are about 20 to about 30 μm or from about 40 to about 70 μm asmeasured by Malvern particle sizing. The skilled artisan would have noproblems in balancing the cohesion of each API employed with the size ofcarrier or type of additive.

In one aspect the carrier particles are present in small amount, such asno more than 90%, preferably 80%, more preferably 70%, more preferably60% more preferably 50% by weight of the total composition. In such “lowcarrier” compositions, the composition preferably also includes at leastsmall amounts of additive materials, to improve the powder propertiesand performance.

In one aspect the compositions according to the invention may furtherinclude one or more additive materials. The additive material may be inthe form of particles which tend to adhere to the surfaces of the activeparticles, as disclosed in WO 1997 003649.

In one aspect the additive material may be coated onto the surface ofcarrier particles present in the composition. This additive coating maybe in the form of particles of additive material adhering to thesurfaces of the carrier particles (by virtue of interparticle forcessuch as Van der Waals forces), as a result of a blending of the carrierand additive. Alternatively, the additive material may be smeared overand fused to the surfaces of the carrier particles, thereby formingcomposite particles with a core of inert carrier material and additivematerial on the surface. For example, such fusion of the additivematerial to the carrier particles may be achieved by co-millingparticles of additive material and carrier particles. In someembodiments, all three components of the powder (active, carrier andadditive) are processed together so that the additive becomes attachedto or fused to both the carrier particles and the active particles. Forthe avoidance of doubt, fine particles obtained from the carrier should,for the purpose of this disclosure, be considered as additive material.

In one aspect the formulation or pharmaceutical composition may comprisetwo or more actives that have been conditioned independently to varyextents and subsequently combined. For example, an active may becombined with pharmaceutically slower acting active to provide acombination which has the benefit of rapid onset of action but alsoconveying the benefit of low recurrence due to their longer half-life.

In one aspect the compositions according to the present invention areprepared by simply blending particles of conditioned active of aselected appropriate size with particles of other powder components,such as additive and/or carrier particles. The powder components may bepre-blended by a gentle mixing process, for example in a tumble mixersuch as a Turbula®. In such a gentle mixing process, there is generallysubstantially no reduction in the size of the particles being mixed. Inaddition, the powder particles do not tend to become fused to oneanother, but they rather agglomerate as a result of cohesive forces suchas Van der Waals forces. Depending on the degree of cohesion between theparticles of API, cohesive agglomerates may behave like largerparticles. These larger particles are therefore unable to reach thedesired site of action with in the pulmonary system resulting oninefficient drug deposition. A benefit of the present invention is theagglomerates are spread over the surface of the excipient resulting indispersion whereby the particles of API are less likely to adhere toeach other. These dispersed particles readily release from the excipientupon actuation of the inhaler device used to dispense the composition.

A number of measures may be taken to ensure that the compositionsaccording to the present invention have good flow and dispersionproperties and these are discussed herein. One or more of these measuresmay be adopted in order to obtain a composition with properties thatensure efficient and reproducible drug delivery to the lung.

In one aspect carrier particles are included to improve the flow anddispersion properties of the compositions of the present invention.

Powder flow problems associated with compositions comprising largeramounts of fine material, such as up to from 5 to 20% by total weight ofthe formulation. This problem may be overcome by the use of largefissured lactose carrier particles, as discussed in earlier patentapplications published as WO 2001 078694, WO 2001 078695 and WO 2001078696.

In one aspect powder density is increased, even doubled, for examplefrom 0.3 g/cm³ to over 0.5 g/cm³. Other powder characteristics arechanged, for example, the angle of repose is reduced and contact angleincreased.

Improved powder handling characteristics and dispensed dosingreproducibility means:

(i) an improvement in powder flow as determined by an increase in powderfill weight for the same volume of a dispensed formulation; or

(ii) Alternatively, improved powder handling characteristics anddispensed dosing reproducibility means an improvement in powder flow asdetermined by a decrease in powder fill weight variation of a dispensedformulation. A decrease in powder fill weight variation is observed whenthe range between the largest and smallest powder fill weights narrows;or(iii) Alternatively, improved powder handling characteristics anddispensed dosing reproducibility means an improvement in powder flow asdetermined by an increase in powder fill weight accuracy of a dispensedformulation. An increase in powder fill weight accuracy is observed whenthe degree of closeness of measurements of the powder fill weights moreclosely match that which is expected for the powder dispensing chamberand the bulk density of the sample powder; or(iv) Alternatively, improved powder handling characteristics anddispensed dosing reproducibility means an improvement in powder flow isdetermined by an increase in powder fill weight precision of a dispensedformulation. An increase in powder fill weight precision is observedwhen the repeated dispensed measurements under unchanged conditions i.e.powder dispensing chamber and the bulk density of the sample powder,show more similar results; or(v) Alternatively, improved powder handling characteristics anddispensed dosing reproducibility means an improvement in powder flow isdetermined by improved dose disaggregation of a dispensed formulation asdetermined by improved blister weight evacuation.

Improved powder handling characteristics may also mean any combinationof properties mentions in paragraphs (i) to (v) above, since these arenot mutually exclusive. All these benefits mentioned in paragraphs (i)to (v) above with respect to improving dispensed dosing reproducibilityof the inhalable formulation from an automated powder filling apparatushave been surprisingly found attributable by the use of a stearate, andin particular use of magnesium stearate in an inhalable formulation.

Force Control Agents

The compositions according to the present invention may include additivematerials that control the cohesion and adhesion of the particles of thepowder.

The tendency of fine particles to agglomerate means that the FPF of agiven dose can be highly unpredictable and a variable proportion of thefine particles will be administered to the lung. This is observed, forexample, in formulations comprising pure drug in fine particle form.Such formulations exhibit poor flow properties and poor FPF.

The additive material or FCA may be in the form of particles which tendto adhere to the surfaces of the active particles, as disclosed in WO97/03649. Alternatively, it may be coated on the surface of the activeparticles by, for example a co-milling method as disclosed in WO02/43701.

Advantageously, the FCA is an anti-friction agent or glidant and willgive the powder formulation better flow properties in the inhaler. Thematerials used in this way may not necessarily be usually referred to asanti-adherents or anti-friction agents, but they will have the effect ofdecreasing the cohesion between the particles or improving the flow ofthe powder and they usually lead to better dose reproducibility andhigher FPFs.

The reduced tendency of the particles to bond strongly, either to eachother or to the device itself, not only reduces powder cohesion andadhesion, but can also promote better flow characteristics. This leadsto improvements in the dose reproducibility because it reduces thevariation in the amount of powder metered out for each dose and improvesthe release of the powder from the device. It also increases thelikelihood that the active material, which does leave the device, willreach the lower lung of the patient.

In one aspect the FCA comprises a metal stearates such as magnesiumstearate, phospholipids, lecithin, colloidal silicon dioxide and sodiumstearyl fumarate, and are described more fully in WO 1996 023485, whichis hereby incorporated by reference.

The optimum amount of additive material or FCA will depend upon theprecise nature of the material used and the manner in which it isincorporated into the composition. In one aspect the the powderadvantageously includes not more than 8%, more advantageously not morethan 5%, more advantageously not more than 3%, more advantageously notmore than 2%, more advantageously not more than 1%, and moreadvantageously not more than 0.5% FCA by weight of the formulation. Inone aspect the powder contains about 1% FCA by weight of theformulation. In other embodiments, the FCA is provided in an amount fromabout 0.1% to about 10%, and preferably from about 0.5% to 8%, mostpreferably from about 1% to about 5% by weight of the formulation.

When the FCA is micronised leucine or lecithin, it is preferablyprovided in an amount from about 0.1% to about 10% by weight of theformulation. Preferably, the FCA comprises from about 3% to about 7%,preferably about 5%, of micronised leucine. Preferably, at least 95% byweight of the micronised leucine has a particle diameter of less than150 μm, preferably less than 100 μm, and most preferably less than 50 μmas determined by laser diffraction particle size analysis, for example aSpraytec with Inhalation Cell, Malvern Instruments, Malvern, UK.

In one aspect magnesium stearate or sodium stearyl fumarate is used asthe FCA, it is preferably provided in an amount from about 0.05% toabout 10%, from about 0.15% to about 7%, from about 0.25% to about 6%,or from about 0.5% to about 5% by weight of the formulation. In oneaspect, the composition includes an FCA, such as magnesium stearate (upto 10% w/w) or leucine, said FCA being jet-milled with the particles ofconditioned active prior to addition to the Comil®.

In one aspect the FCA may comprise or consist of one or more surfaceactive materials, in particular materials that are surface active in thesolid state, which may be water soluble or water dispersible, forexample lecithin, in particular soya lecithin, or substantially waterinsoluble, for example solid state fatty acids such as oleic acid,lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid, orderivatives (such as esters and salts) thereof, such as glycerylbehenate. Specific examples of such surface active materials arephosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerolsand other examples of natural and synthetic lung surfactants; lauricacid and its salts, for example, sodium lauryl sulphate, magnesiumlauryl sulphate; triglycerides such as Dynsan 118 and Cutina HR; andsugar esters in general. Alternatively, the FCA may comprise or consistof cholesterol. Other useful FCAs are film-forming agents, fatty acidsand their derivatives, as well as lipids and lipid-like materials. Insome embodiments, a plurality of different FCAs can be used.

Advantageously, in the “carrier free” formulations, at least 90% byweight of the particles of the powder have a particle size less than 63μm, preferably less than 30 μm and more preferably less than 10 μm. Asindicated above, the size of the particles of conditioned active (or itspharmaceutically acceptable salts) in the powder should be within therange of about from 0.1 μm to 5 μm for effective delivery to the lowerlung. Where the additive material is in particulate form, it may beadvantageous for these additive particles to have a size outside thepreferred range for delivery to the lower lung.

Understanding the principles outlined in this disclosure, the skilledartisan would appreciate the parameters that require amendment in orderto produce a suitable formulation.

In one aspect the use of magnesium stearate is disclosed in an inhalableformulation to improve dosing consistency when dispensing from highthroughput automated dispensers.

In one aspect the use of magnesium stearate in an amount of about 0.05%to about 15%, from about o.io % to about 7%, from about 0.15% to about6%, or from about 0.17% to about 5% by weight of the formulation isdisclosed to improve dosing speed, dosing precision and/or dosingaccuracy of an inhalable formulation when dosing from a high throughputautomated dispenser.

In one aspect the presence of magnesium stearate increases the densityof the formulation as compared to a formulation without magnesiumstearate. The increase in the density may be confirmed by determiningthe tapped density before and after the addition of magnesium stearateto the formulation.

Without wishing to be bound by theory, the lubricant propertiesfacilitate interparticle slippage allowing the particles to bed downwith greater efficiency and thereby occupy a smaller space for anequivalent amount/mass of powder without magnesium stearate. Thisincreased density allows for greater amounts of powder to be dispensedin a predetermined space of the dosing machine.

In one aspect the presence of magnesium stearate moderates the fillweights between formulations of various fines levels. The presence ofmagnesium stearate minimises the variation in the fill weights betweenformulations of various fines levels. In other words, a formulationcontaining 10% fines will have a similar density to a formulationcontaining 15% fines. Similar densities have the distinct advantage thatthe powder filling operator avoids the need to change filling equipment,for example powder filling heads, unlike a formulation without magnesiumstearate.

In one aspect of the present invention, different formulations batchescan be manufactured to have similar/identical densities due to themoderating effect of magnesium stearate. The inclusion of magnesiumstearate removes the need to replace filling equipment componentsbetween batches because inter-batch variation with respect toformulation density can now be removed.

Delivery Devices

The inhalable compositions in accordance with the present invention arepreferably administered via a dry powder inhaler (DPI), but can also beadministered via a pressurized metered dose inhaler (pMDI), or even viaa nebulised system.

Blisters, capsules, reservoir dispensing systems and the like areprovided, comprising doses of the compositions according to theinvention.

Inhaler devices are provided for dispensing doses of the compositionsaccording to the invention. In one embodiment of the present invention,the inhalable compositions are administered via a dry powder inhaler(DPI).

Dry Powder Inhalers

The compositions according to the present invention may be administeredusing active or passive DPIs. As it has now been identified how one maytailor a dry powder formulation to the specific type of device used todispense it, this means that the perceived disadvantages of passivedevices where high performance is sought may be overcome.

Preferably, these FPFs are achieved when the composition is dispensedusing an active DPI, although such good FPFs may also be achieved usingpassive DPIs, especially where the device is one as described in theearlier patent application published as WO 2005 037353 and/or the drypowder composition has been formulated specifically for administrationby a passive device.

In one embodiment of the invention, the DPI is an active device, inwhich a source of compressed gas or alternative energy source is used.Examples of suitable active devices include Aspirair™ (Vectura) and theactive inhaler device produced by Nektar Therapeutics (as disclosed inU.S. Pat. No. 6,257,233), and the ultrasonic Microdose™ or Oriel™devices.

In an alternative embodiment, the DPI is a passive device, in which thepatient's breath is the only source of gas which provides a motive forcein the device. Examples of “passive” dry powder inhaler devices includethe Rotahaler and Diskhaler™ (GlaxoSmithKline) and the Turbohaler™(Astra-Draco) and Novolizer (Viatris GmbH) and GyroHaler™ (Vectura).

The dry powder formulations may be pre-metered and kept in capsules orfoil blisters which offer chemical and physical protection whilst notbeing detrimental to the overall performance. Alternatively, the drypowder formulations may be held in a reservoir-based device and meteredon actuation. Examples of “reservoir-based” inhaler devices include theClickhaler™ (Innovata) and Duohaler™ (Innovata), and the Turbohaler™(Astra-Draco). Actuation of such reservoir-based inhaler devices cancomprise passive actuation, wherein the patient's breath is the onlysource of energy which generates a motive force in the device.

Dry powder inhalers can be “passive” devices in which the patient'sbreath is the only source of gas which provides a motive force in thedevice. Examples of “passive” dry powder inhaler devices include theRotahaler and Diskhaler (GlaxoSmithKline), the Monohaler (MIAT), theGyrohaler (trademark) (Vectura) the Turbohaler (Astra-Draco) andNovolizer (trade mark) (Viatris GmbH). Alternatively, “active” devicesmay be used, in which a source of compressed gas or alternative energysource is used. Examples of suitable active devices include Aspirair(trade mark) (Vectura Ltd) and the active inhaler device produced byNektar Therapeutics (as covered by U.S. Pat. No. 6,257,233).

It is generally considered that different compositions performdifferently when dispensed using passive and active type inhalers.Passive devices create less turbulence within the device and the powderparticles are moving more slowly when they leave the device. This leadsto some of the metered dose remaining in the device and, depending onthe nature of the composition, less deagglomeration upon actuation.However, when the slow moving cloud is inhaled, less deposition in thethroat is often observed. In contrast, active devices create moreturbulence when they are activated. This results in more of the metereddose being extracted from the blister or capsule and betterdeagglomeration as the powder is subjected to greater shear forces.However, the particles leave the device moving faster than with passivedevices and this can lead to an increase in throat deposition.

Particularly preferred “active” dry powder inhalers are referred toherein as Aspirair® inhalers and are described in more detail in WO01/00262, WO 02/07805, WO 02/89880 and WO 02/89881, the contents ofwhich are hereby incorporated by reference. It should be appreciated,however, that the compositions of the present invention can beadministered with either passive or active inhaler devices.

Other Inhalers

In a yet further embodiment, the compositions are dispensed using apressurised metered dose inhaler (pMDI), a nebuliser or a soft mistinhaler. Drug doses delivered by pressurised metered dose inhalers tendto be of the order of 1 lug to 3 mg. Examples of suitable devicesinclude pMDIs such as Modulite® (Chiesi), SkyeFine™ and SkyeDry™(SkyePharma). Nebulisers such as Porta-Neb®, Inquaneb™ (Pari) andAquilon™, and soft mist inhalers such as eFlow™ (Pari), Aerodose™(Aerogen), Respimat® Inhaler (Boehringer Ingelheim GmbH), AERx® Inhaler(Aradigm) and Mystic™ (Ventaira Pharmaceuticals, Inc.).

Compositions suitable for use in these devised include solutions andsuspensions, both of which may be dispensed using a pressurised metereddose inhaler (pMDI). The pMDI compositions according to the inventioncan comprise the dry powder composition discussed above, mixed with ordissolved in a liquid propellant.

In one embodiment, the propellant is CFC-12 or an ozone-friendly, nonCFC propellant, such as 1,1,1,2-tetrafluoroethane (HFC 134a),1,1,1,2,3,3,3 heptafluoropropane (HFC-227), HCFC-22(difluororchloromethane), HFA 152 (difluoroethane and isobutene) orcombinations thereof. Such formulations may require the inclusion of apolar surfactant such as polyethylene glycol, diethylene glycolmonoethyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylenesorbitan monooleate, propoxylated polyethylene glycol, andpolyoxyethylene lauryl ether for suspending, solubilising, wetting andemulsifying the active agent and/or other components, and forlubricating the valve components of the pMDI.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

FIG. 1 discloses a graphical comparison of the blister fill weightsobtained for formulations containing o, 0.1, 0.5, 1 and 2% (w/w)magnesium stearate and 10, 15, 20 and 25% (w/w) lactose fines (S400) inan Omnidose automated powder filling apparatus. Individual fill weightsare represented to illustrate the variation in data. The fill weightsfor formulations containing magnesium stearate are higher than fillweights for the formulation without magnesium stearate demonstrating theincreased density obtainable with magnesium stearate containingformulation. The variation in fill weight data points increases withincreasing levels of lactose fines (S400) for the formulations that donot contain magnesium stearate. This fill weight variation iscounteracted by the use of magnesium stearate in formulations when usedin an amount of 0.1 to 2% (w/w) of the formulation.

FIG. 2 discloses a separate graphical comparison of the blister fillweights presented in FIG. 1.

FIG. 3 discloses a graphical comparison of the poured density obtainedfor formulations containing 0, 0.1, 0.5, 1 and 2% (w/w) magnesiumstearate and 10, 15, 20 and 25% (w/w) lactose fines.

FIG. 4 discloses a graphical comparison of the tapped density obtainedfor formulations containing 0, 0.1, 0.5, 1 and 2% (w/w) magnesiumstearate and 10, 15, 20 and 25% (w/w) lactose fines.

FIG. 5 discloses a plot of magnesium stearate concentration on the xaxis against percentage blister evacuation on the y axis. Blue dotsindicate 10% (w/w) S400 and red dots indicate 30% (w/w) S400. N=10 ateach magnesium stearate level for each concentration of S400. Datapoints are offset on the x axis to aid visualisation, this is not anindication of minute differences in magnesium stearate concentration.

FIG. 6 discloses plot of magnesium stearate concentration on the x axisagainst blister weight as a percentage of mean blister weight (for eachexperimental run) on the y axis. Blue dots indicate 10% (w/w) S400 andred dots indicate 30% (w/w) S400. N=30 at each magnesium stearate levelfor each concentration of S400. Data points are offset on the x axis toaid visualisation, this is not an indication of minute differences inmagnesium stearate concentration.

FIG. 7 discloses a Malvern Mastersizer particle size distribution of themagnesium stearate used throughout these experiments as determined bywet analysis measured in Cyclohexane.

FIG. 8 discloses a Sympatec particle size distribution of magnesiumstearate used throughout these experiments as determined by dryanalysis. The dry method was performed at a dispersion pressure of 4bar.

FIG. 9 discloses the individual fill weights obtained for formulationscomprising SV003 carrier lactose, with either 5% or 20% (w/w) additionalfines (S400), with either 0.0%, 0.1%, 0.5% or 1.0% (w/w) magnesiumstearate. The figure shows that SV003, a formulation possessing levelsof inherent fines is able to fill reproducibly even when challenged withthe addition of 5% (w/w) lactose fines (S400) and 0.8 (w/w) drug(fluticasone propionate). Whereas the same formulation comprisingadditional of 20% (w/w) lactose fines (S400) and 0.8 (w/w) drug(fluticasone propionate) requires a stearate (magnesium stearate) at1.0% (w/w) to improve the dosing reproducibility.

FIG. 10 discloses the individual fill weights obtained for formulationscomprising LH200 (with 14% fines) carrier lactose, with either 5% or 20%(w/w) additional fines (S400), with either 0.0%, 0.1%, 0.5% or to %(w/w) magnesium stearate. The figure shows that LH200, a formulationpossessing levels of inherent fines is able to fill reproducibly evenwhen challenged with the addition of 5% (w/w) lactose fines (S400) and0.8 (w/w) drug (fluticasone propionate). Whereas the same formulationcomprising additional of 20% (w/w) lactose fines (S400) and 0.8 (w/w)drug (fluticasone propionate) requires a stearate (magnesium stearate)at 0.5% (w/w) to improve the dosing reproducibility and 1.0% (w/w)magnesium stearate produces an acceptable formulation.

FIG. 11 discloses the individual fill weights obtained for formulationscomprising ML001 carrier lactose, with either o %, 2% or 12% (w/w)additional fines (S400), with either 0.0%, 0.1%, 0.5% or 1.0% (w/w)magnesium stearate. The figure shows that ML001, a formulationpossessing levels of inherent fines is able to fill reproducibly evenwhen challenged with the addition of 2% (w/w) lactose fines (S400) and0.8 (w/w) drug (fluticasone propionate). Whereas the same formulationcomprising additional of 12% (w/w) lactose fines (S400) and 0.8 (w/w)drug (fluticasone propionate) requires a stearate (magnesium stearate)at 1.0% (w/w) to improve the dosing reproducibility and produce anacceptable formulation.

EXAMPLES

Measures that may be taken to ensure that the compositions according tothe invention have good flow and dispersion properties involve thepreparation or processing of the powder particles, and in particular ofthe active and fine lactose particles. The following examples illustratethe invention.

Example 1

Blending Procedure

Formulations were manufactured to a 300 g scale using the Comil andDiosna Pl/6 in ratios according to Table 1 below:

TABLE 1 Blended Compositions comprising fluticasone propionate (FP),magnesium stearate (MgSt), S400 fine lactose and SV003 Carrier Lactose.Formulation Constituents (% w/w) MgSt FP S400 SV003 0 0.8 10 89.20 0 0.815 84.20 0 0.8 20 79.20 0 0.8 25 74.20 0.1 0.8 10 89.10 0.1 0.8 15 84.100.1 0.8 20 79.10 0.1 0.8 25 74.10 0.5 0.8 10 88.70 0.5 0.8 15 83.70 0.50.8 20 78.70 0.5 0.8 25 73.70 1 0.8 10 88.20 1 0.8 15 83.20 1 0.8 2078.20 1 0.8 25 73.20 2 0.8 10 87.20 2 0.8 15 82.20 2 0.8 20 77.20 2 0.825 72.20 Fluticasone propionate was sieved using a 500 μm sieve prior toincorporation into each blend.

Half the SV003 was processed in a Comil, after which the magnesiumstearate, fluticasone propionate, Sorbolac 400 and the remaining SV003were added in sequence. The Comil was operated at woo rpm using a 457 nmscreen.

The Comiled material was transferred into a 1 litre Diosna bowl andblended at 1457 rpm for 7 minutes 48 seconds. The blended material wasremoved for storage in sealed glass amber jars at ambient laboratoryconditions.

Observations

Physical characterisation and comparison to similar blends withoutmagnesium stearate yielded the following observations:

The blends containing magnesium stearate exhibited generally higher bulkdensity measurements which were largely independent of the change infine particle content until relatively high concentrations of 5400 asdemonstrated in FIG. 3. The effect was more pronounced at the 2% w/wmagnesium stearate level.

The blends containing magnesium stearate exhibited generally highertapped density measurements which increased with the increase in fineparticle content until relatively high concentrations of 5400. This wascompared to a general downward trend in tapped density with increasedfine particle content for comparable non-magnesium stearate blends asdemonstrated in FIG. 4. The effect was more pronounced at the 2% w/wmagnesium stearate level.

TABLE 2 Filling results for batches containing 0, 0.1, 0.5, 1 and 2%(w/w) magnesium stearate Batch Details SV003 Omnidose Filling ResultsMgSt FP S400 (% Mean Min Max RSD (% w/w) (% w/w) (% w/w) w/w) (mg) (mg)(mg) % 0 0.80 10 89.20 12.08 11.78 12.22 0.60 0 0.80 15 84.20 11.64 7.4312.56 11.18 0 0.80 20 79.20 8.60 3.08 12.72 39.61 0 0.80 25 74.20 7.070.77 12.45 46.09 0.1 0.80 10 89.10 12.77 12.57 12.93 0.69 0.1 0.80 1584.10 13.32 13.11 13.46 0.62 0.1 0.80 20 79.10 13.81 13.67 13.95 0.370.1 0.80 25 74.10 13.81 13.63 14.04 0.44 0.5 0.80 10 88.70 13.00 12.6513.29 1.23 0.5 0.80 15 83.70 13.78 13.17 14.02 1.19 0.5 0.80 20 78.7014.46 14.21 14.95 0.67 0.5 0.80 25 73.70 15.17 14.68 15.34 0.58 1.0 0.8010 88.20 13.19 12.96 13.42 0.70 1.0 0.80 15 83.20 13.96 12.70 14.18 1.091.0 0.80 20 78.20 14.62 14.30 14.78 0.54 1.0 0.80 25 73.20 15.23 15.0315.37 0.41 2.0 0.80 10 87.20 14.02 13.83 14.16 0.51 2.0 0.80 15 82.2014.47 14.29 14.65 0.47 2.0 0.80 20 77.20 15.03 14.74 15.16 0.50 2.0 0.8025 72.20 15.47 15.27 15.68 0.49

TABLE 3 Density results for batches containing o, 0.1, 0.5, 1 and 2%(w/w) magnesium stearate Batch Details Density Results S400 SV003 PouredTapped Hausner Carrs MgSt (% FP (% (% (% Density Density Ratio Indexw/w) w/w) w/w) w/w) (g/ml) (g/ml) (AU) (%) 0 0.80 10 89.20 0.667 0.87471.3 23.8 0 0.80 15 84.20 0.619 0.9174 1.5 32.6 0 0.80 20 79.20 0.5940.9009 1.5 34.1 0 0.80 25 74.20 0.554 0.9103 1.6 39.1 0.1 0.80 10 89.100.747 0.9433 1.3 20.8 0.1 0.80 15 84.10 0.708 0.9825 1.4 27.9 0.1 0.8020 79.10 0.698 0.9966 1.4 30.0 0.1 0.80 25 74.10 0.601 0.9440 1.6 36.40.5 0.80 10 88.70 0.763 0.9432 1.2 19.1 0.5 0.80 15 83.70 0.770 1.00271.3 23.3 0.5 0.80 20 78.70 0.769 1.0017 1.3 23.3 0.5 0.80 25 73.70 0.7581.0515 1.4 27.9 1.0 0.80 10 88.20 0.737 0.9321 1.3 20.9 1.0 0.80 1583.20 0.768 0.9915 1.3 22.5 1.0 0.80 20 78.20 0.768 1.0317 1.3 25.5 1.00.80 25 73.20 0.756 1.0838 1.4 30.2 2.0 0.80 10 87.20 0.773 1.0304 1.325.0 2.0 0.80 15 82.20 0.774 1.0166 1.3 23.9 2.0 0.80 20 77.20 0.7651.0611 1.4 27.9 2.0 0.80 25 72.20 0.751 1.0572 1.4 28.9

TABLE 4 Particle size analysis results for batches containing o, 0.1,0.5, 1 and 2% (w/w) magnesium stearate Batch Details Particle SizeResults MgSt FP (% S400 (% SV003 ×10 ×50 ×90 <10 μm (% w/w) w/w) wily)(° why) (μm) (μm) (μm) (%) 0 0.80 10 89.20 7.22 56.33 95.32 12.34 0 0.8015 84.20 4.92 53.35 93.53 16.51 0 0.80 20 79.20 3.92 50.11 91.44 20.22 00.80 25 74.20 3.23 45.79 89.78 24.47 0.1 0.80 to 89.10 6.57 55.07 92.1113.16 0.1 0.80 15 84.10 4.57 51.90 90.03 17.59 0.1 0.80 20 79.10 3.6348.51 89.14 21.61 0.1 0.80 25 74.10 3.12 43.73 86.43 25.64 0.5 0.80 to88.70 7.87 55.97 93.07 11.73 0.5 0.80 15 83.70 5.19 52.98 91.30 16.160.5 0.80 20 78.70 3.88 49.88 89.22 20.46 0.5 0.80 25 73.70 3.34 45.7286.07 24.00 1.0 0.80 10 88.20 8.38 56.42 92.50 11.25 1.0 0.80 15 83.205.09 53.56 93.52 16.17 1.0 0.80 20 78.20 3.75 49.86 91.99 20.88 1.0 0.8025 73.20 3.33 45.34 89.34 24.39 2.0 0.80 10 87.20 6.30 55.86 95.65 13.362.0 0.80 15 82.20 3.83 51.90 92.87 19.15 2.0 0.80 20 77.20 2.93 47.5889.03 23.95 2.0 0.80 25 72.20 2.69 42.91 86.95 27.59Conclusions

The addition of magnesium stearate at an optimised level can be used tocontrol or negate the influence of fine excipient particles informulations with respect to the formulation density and flowcharacteristics; thus producing formulations which overcome many of theproblems associated with volume based filling equipment such as changesin fill mass and dose variability caused by poor flow characteristics.

It is also proposed that the optimum level of magnesium stearaterequired is dependent on the quantity of fine material present in theinhaled formulation.

Example 2

Formulation blends (200 g) with and without magnesium stearate weremanufactured as detailed in Table 2 with a selection of theseformulations containing 2% and 5% MgSt (w/w) respectively.

TABLE 5 Examples of formulation content percentage % w/w SorbolacMagnesium stearate SV003 % g % g % g 0 0 2 4 98 196 15 30 2 4 83 16618.5 37 2 4 79.5 159 25 50 2 4 73 146 37.5 75 2 4 60.5 121 50 100 2 4 4896 62.5 125 2 4 35.5 71 75 150 2 4 23 46 87.5 175 2 4 10.5 21 0 0 5 1095 190 15 30 5 10 80 160 18.5 37 5 10 76.5 153 25 50 5 10 70 140 37.5 755 10 57.5 115 50 100 5 10 45 90 62.5 125 5 10 32.5 65 75 150 5 10 20 4087.5 175 5 10 7.5 15 100 200 0 0 0 0

Respitose SV003 (supplied by DFE Pharma) was used as the coarse fractionand this was particle sized before blending. Respitose SV003 was sievedusing a seize shaker (e.g. Russel Finex) to produce a 45-63 μm sievedfraction. This was a two stage process using a 45 μm sieve to remove the<45 μm material. The material that did not pass the sieve was retainedand passed through a 63 μm sieve. The sieved fraction that was retainedwas used as the coarse lactose for the placebo formulations. A particlesize determination was made of the sieved fraction with the resultsrecorded.

Sorbolac 400 (supplied by Meggle) was used as the fine fraction and aparticle size determination was made before blending with the resultsrecorded.

Magnesium Stearate (supplied by Peter Greven) was used as a forcecontrol agent and a particle size determination was made before blendingwith the results recorded. The Magnesium Stearate was added at amountsof 2% and 5% w/w.

Fluticasone Propionate (supplied by Sterling) was used as the activepharmaceutical ingredient. A particle size determination was made beforeblending with the results recorded.

TABLE 6 Blend compositions Formulation Constituents (% w/w) MagnesiumFluticasone Stearate Propionate S400 SV003 0 0.8 10 89.20 0 0.8 15 84.200 0.8 20 79.20 0 0.8 25 74.20 0.5 0.8 10 88.70 0.5 0.8 15 83.70 0.5 0.820 78.70 0.5 0.8 25 73.70 1 0.8 10 88.20 1 0.8 15 83.20 1 0.8 20 78.20 10.8 25 73.20 2 0.8 10 87.20 2 0.8 15 82.20 2 0.8 20 77.20 2 0.8 25 72.200 2.4 30 267.6 0 2.4 45 252.6 0 2.4 60 237.6 0 2.4 75 222.6 1.5 2.4 30266.1 1.5 2.4 45 251.1 1.5 2.4 60 236.1 1.5 2.4 75 221.1 3 2.4 30 264.63 2.4 45 249.6 3 2.4 60 234.6 3 2.4 75 219.6 6 2.4 30 261.6 6 2.4 45246.6 6 2.4 60 231.6 6 2.4 75 216.6

The formulations were manufactured to a 300 g scale in the amountsoutlined in Table 2 (above) using a Comil and a Diosna Pl/6.

Firstly, the fluticasone propionate was sieved the using a 500 μm sieve.

Half of the SV003 fraction was Comiled, followed sequentially by themagnesium stearate, fluticasone propionate, Sorbolac 400 and theremaining SV003 at 1000 rpm using a Comil 457 μm screen.

This comiled material was transferred to a 1 litre Diosna bowl andblended at 1457 rpm for 7 min 48 sec. The blending was processed with ablanking plate instead of the chopper.

The blended material was removed for storage in sealed glass amber jarsat ambient laboratory conditions. Each Blend was tested for contentuniformity

An Omnidose automated powder filling apparatus (HarroHöfliger) was setup for filling unit doses using a 16 mm³ blister format dosing drum andstandard equipment settings.

The Omnidose automated powder filling apparatus hopper was charged witheach formulation in turn and a dose weight evaluation was carried usinga 5 figure analytical balance. The results are reported in FIG. 1.

Conclusions

Physical characterisation and comparison to similar blends withoutmagnesium stearate yielded the following observations. The blendscontaining magnesium stearate exhibited generally higher bulk densitymeasurements which were largely independent of the change in fineparticle content until relatively high concentrations of S400. Theeffect was more pronounced at the 2% w/w magnesium stearate level. Theblends containing magnesium stearate exhibited generally higher tappeddensity measurements which increased with the increase in fine particlecontent until relatively high concentrations of S400. This was comparedto a general downward trend in tapped density with increased fineparticle content for comparable non-magnesium stearate blends. Theeffect was more pronounced at the 2% w/w magnesium stearate level. Asignificant reduction in flow energy which follows a more linearrelationship compared to non-magnesium stearate blends.

It is proposed that the addition of magnesium stearate at an optimisedlevel could be used to control or negate the influence of variable fineparticle lactose and/or API content in formulations with respect to theformulation density and flow characteristics; thus producingformulations which overcome many of the inherent problems associatedwith volume based filling equipment such as changes in fill mass anddose variability caused by poor flow characteristics.

It is also proposed that the optimum level of magnesium stearaterequired is dependent on the particle size distribution of the carrier.

Example 3

The 3Pi dosator is a volumetric filling system which utilises a tube tocollect and transfer a pre-determined volume of powder from a powderreservoir into a blister or capsule.

Within the filling tube is a piston which can be used to apply an amountof compression to the formulation. If the correct level of compressionis applied, dose cohesion and dose weight uniformity is improved. Ifhowever, dose compression is applied incorrectly, the compression cancause hard unaerosolisable doses that reside in the blister or capsule.

Blend Manufacture

Coarse fraction: Lactohale LH200 (supplied by Domo) was used as thecoarse fraction and was particle sized according to before blending.

Fine fraction: Sorboiac 400 (supplied by Meggle) was used as the finefraction and was particle sized before blending.

Magnesium Stearate: Magnesium stearate (supplied by Peter Greven) wasused to assist dispensed inhalable dose disaggregation.

Fluticasone Propionate (FP): Fluticasone Propionate (supplied bySterling) was used as the active pharmaceutical ingredient and wasparticle sized before blending.

Formulation Component Particle Size

Particle size data of the formulation components was established priorto manufacture.

TABLE 7 The particle size data of the formulation components. D10 D50090 (μm) (μm) (μm.) Lactohale LE LH00 9.66 71.44 144.82 Sorbolac S4001.91 8.41 19.37 Magnesium Stearate 3.01 9.08 26.23 FluticasonePropionate 0.92 2.06 4.07Blending Procedure

The formulations were manufactured to 300 g scale in the ratio describedin Table 8 below. The fluticasone propionate was sieved using a 500 μmsieve. Half the LH200 was processed using a Comil at woo rpm using a 457μm screen, followed by the magnesium stearate, then followed by thefluticasone propionate, then the Sorbolac 400 and finally with theremaining LH200 all at the Comil conditions mentioned above. Thisprocessed material was transferred into a 1 litre Diosna bowl andblended at 1457 rpm for 8 mins. This blended material was removed forstorage in sealed glass amber jars at ambient laboratory conditions.

TABLE 8 Composition of the manufactured formulations FormulationConstituents (% w/w) Magnesium Fluticasone Fine fraction Coarse fractionStearate Propionate (S400) (LH200) 0.0 0.8 10 89.2 0.0 0.8 20 79.2 0.00.8 30 69.2 0.5 0.8 10 88.7 0.5 0.8 20 78.7 0.5 0.8 30 68.7 2.0 0.8 1087.2 2.0 0.8 20 77.2 2.0 0.8 30 67.2Content Uniformity

Each blend was tested for content uniformity.

TABLE 9 Composition of the manufactured formulations and blenduniformity data for blends comprising 0.0, 0.5 and 2.0% (w/w) magnesiumstearate. Formulation Constituents (% w/w) Content Uniformity Mean %MgSt FP S400 LH200 (% w/w) Theory RSD % 0.0 0.8 10 89.2 0.754 94.20 1.60.0 0.8 20 79.2 0.777 97.10 1.7 0.0 0.8 30 69.2 0.767 95.88 1.0 0.5 0.810 88.7 0.730 91.22 1.9 0.5 0.8 20 78.7 0.763 95.41 3.1 0.5 0.8 30 68.70.753 94.16 3.5 2.0 0.8 10 87.2 0.775 96.91 1.8 2.0 0.8 20 77.2 0.78297.77 1.1 2.0 0.8 30 67.2 0.767 95.89 1.9Blend Particle Size Analysis

The particle size distribution of each blend was tested.

TABLE 10 Composition of the manufactured formulations and particle sizedistribution analysis data for blends comprising 0.0, 0.5 and 2.0% (w/w)magnesium stearate. Formulation Constituents (% w/w) Particle Size MgStFP S400 LH200 D10 (μm) 050 (μm) D90 (μm) 0.0 0.8 10 89.2 8.18 92.41154.27 0.0 0.8 20 79.2 3.79 79.37 146.09 0.0 0.8 30 69.2 2.84 62.86141.77 0.5 0.8 10 88.7 7.81 92.33 153.78 0.5 0.8 20 78.7 3.45 80.30147.35 0.5 0.8 30 68.7 2.68 65.25 143.29 2.0 0.8 10 87.2 5.42 89.81152.75 2.0 0.8 20 77.2 2.53 76.49 148.54 2.0 0.8 30 67.2 2.09 53.17141.55Dosator Setup, Sample Compression Evaluation

The 3Pi Dosator was set up for each experimental run. The hopper wascharged with formulation and a dose weight evaluation was carried outusing a 5 figure analytical balance. Blister samples were sealed using abench top blister sealer.

The process was as follows:

-   -   1. 25 doses to waste, then    -   2. 20 weight samples (Run 1), then    -   3. 10 inhaler blisters filled and sealed with their individual        weights recorded.

Blister shot weights were evaluated in an inhaler device for each set offilling parameters by D[SA using a 4 figure analytical balance asdetailed below:

-   -   Flow rate: 60 Limin    -   Shot time 2 Seconds    -   Replicates: 10

Results are presented in FIG. 5 and FIG. 6

Conclusions

The data presented in FIG. 5 for the o % (w/w) magnesium stearate blendsshows an unacceptable blister evacuation with a high degree ofvariability for both 10% and 30% S400 formulations.

The data presented in FIG. 5 for the 0.5% (w/w) magnesium stearateblends shows that the variability has decreases for the 10% S400formulation and acceptable evacuation for the 30% S400 formulation.

The data presented in FIG. 5 for the 2.0% (w/w) magnesium stearateblends shows consistent evacuation for both the 10% S400 formulation andthe 30% S400 formulation.

FIG. 6 shows a decrease in dose weight variability from o % magnesiumstearate to 0.5% magnesium stearate indicating that 0.5% magnesiumstearate assists in maintaining reproducible doses. As the concentrationof magnesium stearate is further increased to 2.0%, the dosereproducibility is maintained with the exception of two doses thatfailed to leave the dosator pin (30% S400 formulation). This is thoughtto be due to the powder plugs adhering and being pulled back into thepin, an affect known as Capping. This this thought to be as a result ofthe highly cohesive nature of the formulation.

The use of magnesium stearate as a flow aid to assist in dispensedinhalable dose disaggregation is disclosed. This new use dramaticallyimproves capability of the dosator filling apparatus to dispenseaccurate, reproducible and unaerosolisable doses.

Example 4

A variety of formulations comprising either Respitose SV003, RespitoseML001 or Lactohale LH200 as a representative excipient carrier system,with either 0%, 0.1%, 0.5% or 1.0% (w/w) magnesium stearate with varyingamounts of added model fine particle component (S400) were manufacturedand dosed from a Harro Hofliger Omnidose automated powder fillingapparatus.

Blend Manufacture

The various formulations comprised the following constituent parts:

Coarse fraction: either Respitose SV003, Lactohale LH200 (alreadycontaining 14% (w/w) fines) and Respitose ML001 were used as coarsefractions and were subject to particle size analysis before blending(Table 11).

Fine cohesive fraction: Sorbolac 5400 was used as the model finefraction component and was subject to particle size analysis beforeblending (Table 11).

Stearate: Magnesium stearate (supplied by Peter Greven) was used as aforce control agent and a particle size determination was made beforeblending with the results recorded (Table 11).

Model drug: Fluticasone propionate (FP) (supplied by Sterling) was usedas the active pharmaceutical ingredient and a particle sizedetermination was made before blending with the results recorded (Table11).

Formulation Component PSD

Particle size data of the formulation components was established priorto manufacture.

TABLE 11 The particle size data of the formulation components. D₁₀ D₅₀D₉₀ % < 10 (μm) (μm) (μm) μm Respitose SV003 32.01 58.61 91.84 3.83Respitose ML001 4.57 47.59 140.88 17.10 Lactohale LH200 9.66 71.44144.82 10.28 Sorbolac S400 1.53 7.77 18.76 61.74 Magnesium Stearate 1.445.56 18.11 76.44 Fluticasone Propionate 0.9 2.10 4.20 100Blending Procedure

The formulations were manufactured to 300 g scale in the ratiosdescribed in Tables 12, 13 and 14. The fluticasone propionate was sievedusing a 500 μm sieve. Half the coarse lactose was processed using aComil at woo rpm using a 457 μm screen, followed by the magnesiumstearate (where applicable), then followed by the fluticasonepropionate, then the Sorbolac 400 (where applicable), and finally withthe remaining coarse lactose all at the Comil conditions mentionedabove. This processed material was transferred into a 1 litre Diosnabowl and blended at 1457 rpm for 8 mins. This blended material wasremoved for storage in sealed glass amber jars at ambient laboratoryconditions.

Analysis Procedure

Using an FT4 Powder Rheometer (Freeman Technology) a sample of eachmanufactured blend was subjected to the following tests as described inthe FT4 user manual and/or associated Freeman Technology literature.

The FT4 Aeration test determines Basic Flowability Energy, SpecificEnergy, Conditioned Bulk Density, Aerated Energy, Aeration Ratio andNormalised Aeration Sensitivity. The standard 25 mm Aeration program wasoptimised to achieve improved reproducibility over the Freeman method.

The FT4 Permeability test determines the Pressure Drop at compactionpressures from 0.6 kPa to 15 kPa. The standard 25 mm Permeabilityprogram was optimised to achieve improved reproducibility over theFreeman method.

The FT4 Shear test was performed using the standard 25 mm Shear 3 kPaprogram which determines incipient shear stress up to a compactionpressure of 3 kPa.

The FT4 Compressibility test was performed using the standard 25 mmCompressibility 1-15 kPa which determines percentage compressibility upto a compaction pressure of 15 kPa.

Blend Particle PSD

The particle size distribution of each blend was tested and expressed asD₁₀, D₅₀, D₉₀ and %<10 μm. All blends and lactose were measured dry at adispersion pressure of 2 bar.

TABLE 12 Composition of the manufactured formulations (300 g) andparticle size distribution analysis data for blends comprising LH200,S400 fines and 0.0, 0.1, 0.5 and 1.0% (w/w) magnesium stearate. BlendConstituents (% w/w) Blend Particle Size Distribution LH200 D₅₀ D₉₀ MgStFP S400 (14% fines) D₁₀ (μm) (μm) (μm) % <10 μm 0.0 0.8 5 94.2 6.2565.36 141.76 14.21 0.1 0.8 5 94.1 5.92 65.31 142.16 14.75 0.5 0.8 5 93.75.96 65.81 142.31 14.55 1 0.8 5 93.2 5.13 64.25 142.15 15.82 0.0 0.8 2079.2 3.30 38.87 134.16 25.79 0.1 0.8 20 79.1 3.24 41.35 134.96 25.21 0.50.8 20 78.7 3.05 39.92 134.58 26.06 1 0.8 20 78.2 2.89 37.29 133.9527.11

TABLE 13 Composition of the manufactured formulations (300 g) andparticle size distribution analysis data for blends comprising ML001,S400 and 0.0, 0.1, 0.5 and 1.0% (w/w) magnesium stearate. BlendConstituents Blend Particle Size Distribution (% w/w) % MgSt FP S400ML001 D₁₀ (μm) D₅₀ (μm) D₉₀ (μm) <10 μm 0.0 0.8 0 99.2 3.66 46.69 141.4418.59 0.1 0.8 0 99.1 3.65 46.36 140.31 18.62 0.5 0.8 0 98.7 3.54 46.70142.21 18.90 1 0.8 0 98.2 3.11 44.89 139.95 20.20 0.0 0.8 2 97.2 3.4745.15 139.69 19.66 0.1 0.8 2 97.1 3.48 44.77 139.80 19.72 0.5 0.8 2 96.73.27 44.58 140.99 20.36 1 0.8 2 96.2 2.99 42.72 138.57 21.36 0.0 0.8 1287.2 2.80 33.10 130.76 26.15 0.1 0.8 12 87.1 2.83 33.99 131.80 25.70 0.50.8 12 86.7 2.65 33.06 132.33 26.65 1 0.8 12 86.2 2.56 32.31 131.4227.29

TABLE 14 Composition of the manufactured formulations and particle sizedistribution analysis data for blends comprising SV003, 5400 and 0.0,0.1, 0.5 and 1.0% (w/w) magnesium stearate. Blend Constituents BlendParticle Size Distribution (% w/w) % MgSt FP S400 SV003 D₁₀ (μm) D₅₀(μm) D₉₀ (μm) <10 μm 0.0 0.8 5 94.2 14.86 56.94 91.08 8.04 0.1 0.8 594.1 15.42 56.90 90.95 7.87 0.5 0.8 5 93.7 13.45 56.45 90.54 8.52 1 0.85 93.2 13.41 56.64 90.85 8.53 0.0 0.8 20 79.2 3.80 47.73 85.60 21.18 0.10.8 20 79.1 3.91 48.03 85.56 20.64 0.5 0.8 20 78.7 3.56 47.47 85.4121.53 1 0.8 20 78.2 3.32 47.01 85.40 22.50

Compared with the constituent carrier PSDs, the blend PSDs shifted tothe smaller size for those blends that contained increased levels of5400, and also for those blends that contained increased levels ofmagnesium stearate, although the change with magnesium stearate wasnegligible.

The LH200 and ML001 blends have broad size distributions due to theirmilled method of manufacture. The ML001 blends have the greatestconcentration of fine particles and are likely to be the most cohesive.In contrast, SV003 blends have a much narrower distribution because itis a sieved excipient carrier with a narrower size distribution.

Harro Höfliger Omnidose Filling

The Harro Höfliger Omnidose automated powder filling apparatus was setup for filling unit doses using a standard 15 mm³ dosing drum andstandard equipment settings.

The hopper was filled with formulation and a dose weight evaluation wascarried out as follows using a 5 figure analytical balance:

-   -   1. 50 doses to waste    -   2. 24 weight samples (Run 1)    -   3. 100 dosing cycles to waste (equivalent to 400 individual        doses)    -   4. 24 weight samples (Run 2)    -   5. 100 dosing cycles to waste (equivalent to 400 individual        doses)    -   6. 24 weight samples (Run 3)    -   7. 100 dosing cycles to waste (equivalent to 400 individual        doses)    -   8. 24 weight samples (Run 4)    -   9. 100 dosing cycles to waste (equivalent to 400 individual        doses)    -   10. 24 weight samples (Run 5)        Acceptance Criteria

The fill weight data and observations were evaluated in terms of doseweight reproducibility and equipment failure modes. The target fillweight was derived for each lactose grade as the mean fill weightobtained from the lowest percentage S400 content formulation whichcontained no magnesium stearate.

Acceptance limits were based on ±10% of the mean weight. Individualweights falling outside of this range were deemed unacceptable. Commonmodes of failure are caused by poor powder flow within the hopper andevident in the fill weight variability

As a volumetric system the weight of the fixed volume dispensed dose isdirectly proportional to the formulation density, therefore changes indensity have a direct impact on dispensed weight under common dosingconditions.

Conclusions

This example produced a range of formulations to challenge the failurepoint of a drum filling apparatus in terms of dispensed dosereproducibility i.e. the amount of total powder dispensed from the drumfiller into a capsule or blister. This example demonstrates that thepowder filling performance using a drum filling apparatus (e.g. HarroHöfliger Omnidose filling machine) varied with respect to excipient typeand that the dose reproducibility failure point was observed at varyingfine particle contents depending on the lactose carrier used.

The fill weight reproducibility failure is a function of the total fineparticle content causing poor powder flow in the drum filling apparatus'hopper, leading to partial dosing. Some excipient carrier systems havehigher levels of inherent fines (e.g. ML001) contributing to poor powderflow and poorly reproducible dosing.

Blends were manufactured with a range of lactose carriers with differentlevels of inherent and added fines, with and without a stearate, in thiscase magnesium stearate. The addition of magnesium stearate to poorlyperforming formulations improves filling characteristics of inhalableformulations, in particular dispensed dose reproducibility.

What is claimed is:
 1. A method of improving dispensed dosingreproducibility of an inhalable pharmaceutical formulation from anautomated powder filling apparatus, comprising: blending a micronizedpharmaceutically active material, magnesium stearate, and carrierparticles to yield a blended inhalable pharmaceutical formulation,wherein the carrier particles comprise fines, wherein the finesconstitute greater than 10% (w/w) of the total weight of said micronizedpharmaceutically active material, magnesium stearate, and carrierparticles, wherein said magnesium stearate has a D₁₀≤3 μm, D₅₀≤10 μm andD₉₀≤30 μm prior to blending as determined by laser diffraction particlesize analysis, and wherein said magnesium stearate is present in amountof from 0.1% to 50% by weight out of a total weight of the micronizedpharmaceutically active material, magnesium stearate and carrierparticles.
 2. The method of claim 1, wherein the amount of magnesiumstearate present is from 0.1% to 2% by weight of the total weight of themicronized pharmaceutically active material, magnesium stearate andcarrier particles.
 3. The method of claim 1, wherein the magnesiumstearate has a D₁₀≤2 μm, D₅₀≤6 μm and D₉₀≤20 μm as determined by laserdiffraction particle size analysis.
 4. The method of claim 1, whereinthe carrier particles comprise greater than 15% (w/w) fines out of thetotal weight of the micronized pharmaceutically active material,magnesium stearate and carrier particles.
 5. The method of claim 1,wherein said carrier particles have a D₅₀ greater than 45 μm asdetermined by laser diffraction particle size analysis.
 6. The method ofclaim 1, further comprising: loading the blended inhalablepharmaceutical formulation into a Dosator powder filling apparatus; anddispensing the blended inhalable pharmaceutical formulation from aDosator powder filling apparatus.
 7. The method of claim 1, wherein themicronized pharmaceutically active material is selected from the groupconsisting of a long-acting muscarinic antagonist, a long-actingbeta-adrenoceptor agonist and an inhaled corticosteroid.
 8. The methodof claim 1, wherein the micronized pharmaceutically active material isselected from any of budesonide, formoterol fumarate, glycopyrroniumbromide, indacaterol maleate, umeclidinium bromide, vilanteroltrifenatate, tiotropium bromide, salmeterol xinafoate, fluticasonepropionate, and combinations thereof.
 9. The method of claim 1, whereinthe micronized pharmaceutically active material is glycopyrroniumbromide and indacaterol maleate.
 10. The method of claim 1, wherein themicronized pharmaceutically active material is fluticasone furoate andvilanterol trifenatate.
 11. The method of claim 1, wherein themicronized pharmaceutically active material is tiotropium bromide. 12.The method of claim 1, wherein the micronized pharmaceutically activematerial is umeclidinium bromide and vilanterol trifenatate.
 13. Themethod of claim 1, wherein the micronized pharmaceutically activematerial is glycopyrronium bromide.
 14. A method of improving dispenseddosing reproducibility of an inhalable pharmaceutical formulation froman automated powder filling apparatus, comprising: blending a micronizedpharmaceutically active material, magnesium stearate, one or moreadditional stearates, and carrier particles, wherein said micronizedpharmaceutically active material, magnesium stearate, and carrierparticles collectively comprise greater than 10% (w/w) fines, whereinsaid magnesium stearate has a D₁₀≤3 μm, D₅₀≤10 μm and D₉₀≤30 μm prior toblending as determined by laser diffraction particle size analysis,wherein said magnesium stearate is present in amount of from 0.1% to 50%by weight out of a total weight of the micronized pharmaceuticallyactive material, magnesium stearate and carrier particles, and whereinsaid one or more additional stearates are selected from the groupconsisting of calcium stearate and sodium stearate.